NEUROTRANSMITTER SYSTEMS IN THE VISUAL CORTEX OF THE ...

ACTA NEUROBIOL.

EIXP. 1988,

48: 335-370

NEUROTRANSMITTER SYSTEMS IN THE VISUAL CORTEX OF THE CAT: POSSIBLE INVOLVEMENT IN PLASTIC PHENOMENA Jolanta SKANGIEL-KRAMSKA Department of Neurophysiology, Neacki Institute of Experimental Biology Pasteura 3, 02-093 Warsaw, Poland

Key words: visual cortex, neurotransmitter systems, neuronal plasticity, cat

Abstract. The aim of this paper is to review some of the investigations on neurotransmitter systems suggesting their possible role in visual information processing and their putative involvement in the plastic phenomena observed in the primary visual cortex of the cat. The neurotransmitters discussed include excitatory amino acids, y-aminobutyric acid, acetylcholine, noradrenaline and serotonin. The following problems are discussed: (i) the occurrence and localization of the various neurotransmitter system components, (ii) the developmental changes of the components of a given neurotransmitter system, particularly in the critical period, (iii) the effects of manipulating the visual input on neurotransmitter system markers. It seems that especially during the critical period there exists a peculiar pattern of interactions between numerous neurotransmitters and neuromodulators. This may create unique conditions, which enable the visual cortical neurons to change their properties as a results of alterations of the visual input. INTRODUCTION

The understanding of the molecular mechanisms underlying the plastic changes in the brain is still fragmentary and does not permit a consistent hypothesis. However, the increasing number of reports that neu-

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rons may profoundly change neurotransmitter expression and metabolism during development and maturity led Black et al. (15) to suggest that "neurotransmitter mutability may constitute a unique mechanism underlying plasticity in the nervous system". One of the manifestations s f the plastic properties of the brain is the possibility to provoke major alterations in the functional connectivity of the primary visual cortex a s a result of abnormal vision. Especially, the binocular and monocular Normal

6nocularly deprived

Monocularly deprived

1 1 2 3 4 5 6 7

Ocular dominance group

VU

Fig. 1. The acular dominance histograms showing the effect of different rearing condition. Each histogram illustrates the number d visual cortical neurons seen i n each of seven ocular dominance groups, where 1 represents cells exclusively driven by the contralateral eye; 7, represents cells exclusively driven by the i w lateral eye; 4, represents cells equally driven by both eyes. Group 3 and 5 represent cells slightly more strongly dominated by the contralateral and ipsilateral eyes respectively; group 2 and 6 represent neurons very strongly dominated by the contralateral and ipsilateral eyes respectively. W, the number of neurons visually unresponsive. (Adapted from Ref. 16).

deprivation methods give a powerful tool for manipulating the sensory input, and offer experimental paradigms for investigating the plasticity of the visual cortex. The physiological response to these two methods of deprivation is different. Binocular deprivation (BD) results in the loss or severe attenuation of responsiveness of the neurons in the visual cortex, whereas after monocular deprivation (MD) the cortical cells change their preferred. ocularity to the nondeprived eye (Fig. 1). The modification of binocularity and also other receptive field properties of cortical neurons is confined to a period in the early postnatal life, the so-called

"critical period" (58, 164). The critical period in kittens has been found to span from the third week to the fourth month after birth. The mechanisms underlying the two types of deprivation are different. 'MD during the critical period causes a redistribution of the thalamocortical afferents from the two eyes. In normal adult cats the afferemts . from each eye are segregated and form alternating domains, termed ocular dominance (O.D.) columns (122, 123). MD alters this pattern and the O.D. columns representing the functioning eye extend their boundaries and widen at the expense of the adjacent columns, representing the deprived eye. This is a manifestation of the competition of the afferents from the two eyes for synaptic space. The amatomical substrate for O.D. columns has been demonstrated in cats (72, 81 123) and Old World monkeys (50, 82) by using different neuroanatomical techniques (Fig. 2).

Fig. 2. Scheme of the organizat~ionof the primate striate cortex. ODC, ocular dominance columns revealed by unit recordings and neuroanatomical autoradiographic techniques. Shaded regions correspond to cytochrome oxidase staining pattern. I-VI, cortical layers.

Moreover, a surface antigen that identifies O.D. columns has been described (56). BD from birth postpones the onset of the critical period for O.D. plasticity (30, 90). Therefore BD seems to prevent some maturation processes, and the binocularly deprived visual cortex can be regarded as an underdeveloped structure. Thus it can be concluded that visual experience during the critical period is a necessary factor in establishing

fully functioning and stabilized connections within the primary visual cortex (91). Both BD and MD produce changes in the appearance of the nerve terminals. The cortical cells in BD cats show both a low density bf synaptic vesicles (43) and a reduction of the number of synapses associated with each neuron (27), which may be understood as a result of the arrest of neuronal maturation due to the lack of some trophic i'nfluence of the visual afferents on immature neurons (76, 161). In MD cats the synaptic terminals of deprived afferents are also abnormal morphologically and fewer in number (157). The studies of the neurochemical correlates of visual deprivation provide a profitable basis for the search for unified principles, which may help to explain visual cortical plasticity. The present article includes a review of some of the investigations on neurotransmitter systems, suggesting their possible role in the visual information processing and their probable involvement in the plastic phenomena observed in the primary visual cortex. The neurotransmitters discussed include classical mediators: excitatory amino aciddglutamic (Glu) and aspartic acids (Asp)/, y-aminobutyric acid (GABA), acetylcholine (ACh), noradrenaline (NA), serotonin (5-HT). The evidence concerning the involvement of some processes relating to neurotransmission, such as protein phosphorylation, is also considered. The following problems are discussed (i) the occurrence and localiza- . tion of the various neurotransmitter system components (such as the neurotransmitter itself, the neurotransmitter metabolising enzymes and the neurotransmitter receptors) in the primary visual cortex of a normal adult cat, (ii) the developmental changes of the components of' a gi: ven neurotransmitter system, particularly in the critical period, (iii) the effects of manipulating the visual input on neurotransmitter system markers. GLUTAMATE AND/OR ASPARTATE

There is considerable experimental support for the view that glutamate (Glu) and/or aspartate (Asp) are transmitters in the cerebral cortex. Endogenous Glu is released from the rat cerebral cortex following subcortical electrical stimulation (61) or surface administration of K+ (22). Using the method of transmitter-specific retrograde labeling of neurons, Baughman and Gilbert (6) found that, in cats, neurons in layer VI of area 17 projecting to the lateral geniculate nucleus (LGN) use Asp and/or Glu as their transmitters. The results of biochemical studies of the effect of visual cortex ablation particularly on high affini-

ty uptake of [3H]Glu or D-[3H}Asp, also provide evidence for considering GluIAsp as neurotransmitters in the efferents to the LGN, the pulvinar and the superior colliculus in rats (40, 77, 78) and cats (41). Moreover, it appears also that GluIAsp are synaptic transmitters of the cortico-cortical visual pathways in the cat (6, 41, 55). Despite some efforts, earlier reports did not find evidence of the neurotransmitter action of Glu/Asp in the geniculocortical afferents (6, 54). The excitatory amino acids act through several receptors. Four classes of receptors have so far been distinguished. Three are defined by the agonists that activate them: the NMDA, kainate and quisqualate receptors. The fourth class is defined by the antagonist action of L-2-aminophosphonobutyric acid (L-AH). The introduction of potent antagonists of different GluIAsp receptors permits us to reinvestigate the pro-

Fig. 3. Simplified diagram of probable GluIAsp geniculocortical projection to area 17 of the cat. LGN, lateral geniculate nucleus; I-IV, cortical layers (Ref. 160 modif ied).

blem of operaking sites of Glu/Asp in the cortical neuronal circuitry. Recent studies by Tsumoto et al. (160) show that some antagonists of Glu/Asp receptors effectively bloch visually induced and Glu/Asp induced excitation of the cortical cells of the cat. Among the drugs examined kynurenic acid (KYNA) was the most potent. This endogenously occurring L-tryptophan metabolite blocked almost completely the excitatory actions of NMDA and kainate and to a lesser extent the excitation induced by quisqualate. The effectiveness of KYNA in suppressing visual response was related to the types of receptive fields of the cells and their laminar location. A great majority of simple cells are completely blocked by this antagonist (76O/o) whereas only a small

percentage of complex cells react to KYNA with a complete block of their visual responses. The highest proportion of cells completely blocked by KYNA was found in layer IV ab, IV c and the upper part of layer VI whereas most of the cells in the other layers were incompletely suppressed or not suppressed at all. Since the primary geniculocortical afferents project mainly to these layers (80), the above results suggest that visual responses of cortical cells are mediated at least partially by GluIAsp in the cat's visual cortex (Fig. 3). Thus it is reasonable to suppose that alteration in the normal visual input should affect first of all these excitatory amino acid systems. There is accumulating evidence of the role of excitatory amino acid receptors in the plastic phenomena in the brain and special attentiori is focused on NMDA receptors channel which is permeable to Ca++ ions only if the postsynaptic membrane is sufficiently depolarized. Thus the NMDA receptor permits current flow only if there is coincident pre- and postsynaptic activation (26). Therefore it is not surprising that the involvement of NMDA receptors in visual cortical plasticity has been considered. Electrophysiological studies show that the proportion of cells supressed by iontophoretic application of D-2-amino-5-phosphonovalerate (APV) - a potent selective antagonist of NMDA receptors - is much higher in the visual cortex of young kittens than in adult cats. These results suggest that NMDA receptors in the visual cortex during the critical p e r i d are more effective than those of mature cats (159). Furthermore, developmental studies indicate that the APV-sensitive [3H]Glu binding sites are especially numerous during the critical period (17). It can be conjectured that the enhanced effectiveness of NMDA receptors on first order visual cortical neurons is a necessary requirement for plasticity. Interestingly, the BD of cats does not affect the ontogeny of NMDA receptor sites in the visual cortex (17). More information concerning the participation of NMDA receptors in visual cortical plasticity derives from the study of MD animals. In the visual cortex of the kitten the O.D. shift normally occurring in response to monocular vision can be prevented by chronic administration of APV. The effect of APV seems to be dose-dependent (69, 70, 141). Similarly, ketamine-xylazine anaesthesia prevents the O.D. shift in kittens which receive monocular exposure (109). Probably this effect is due to the blockade of NMDA receptors by ketamine (156). Evidence concerning the role of GluIAsp transmission involving NMDA receptors comes also from the model experiments on the amphibian optic system. Antagonist-AVP appears to desegregate reversibly the O.D. columns when applied to the tecta of tadpoles with a grafted supranumerary eye, while chronic application

of agonist-NMDA appears to potentiate the formation of O.D. stripes (23). To sum up, these results seems to indicate that NMDA receptors play a crucial role in O.D. plasticity expression. They also point to the participation of Ca+t ions in the plastic phenomena since NMDA receptor activation raises Ca+t conductance into postsynaptic cells. The resulting Ca+ fluxes may trigger off synaptic modifications. Apart from the investigations concerning the role of NMDA receptors in visual cortical plasticity, there have been studies, conducted by Shaw and Cynader (125), of the possible involvement of glutamate in the O.D. changes. They found that intracortical chronic infusion of L-Glu during the period of monocular vision in young kittens largely prevents the O.D. shift which normally takes place under these conditions. Glutamate probably disrupts normal cortical activity, either by direct excitatory action on cortical neurons or as a consequence of neurotoxic effects, and thus blocks plasticity. Therefore, normal postsynaptic activity seems to be an important factor of cortical plasticity. GABA

There is evidence from morphological, biochemical and electrophysiological stuhes that GABA is a transmitter in the visual cortex. By using immunocytochemical methods and high affinity uptake of exogenous [3H]GABA it has been possible to provide the morphological characteristics of stained neurons and information about their connections. It appears that GABAergic interneurons and terminals are present in all layers of the striate cortex. They form a heterogeneous population with regard to size and synaptic input. Besides a powerful asymmetric, presumably excitatory synaptic input along their dendrites some GABAergic neurons receive synaptic input from other GABAergic neurons not only on their cell bodies but also on their dendrites. Therefore GABAergic neurons are likely to be involved in many different ways in visual information processing (150). Light and electron miroscopic examination of the organization of [3H]GABA transporting neurons in the monkey's cerebral cortex (Macaca) shows that GABAergic neurons form a bidirectional system of connections which join together cells in the superficial and deep layers of the cortical columns (probably representing functional cortical units) (35). A vertical organization of GABAergic neurons has also been reported in the visual cortex of the rhesus monkey (149). GABAergic cells seem to constitute 8-20°/a of all the neurons present in layer IV of the cat visual cortex (42, 148). Glutamic acid decarboxylase (GAD), the enzyme synthezising GABA, is another marker used to localize GABAergic neurons and termi-

nals, because it is confined almost entirely to neurons. Immunocytochemica1 staining with an antiserum to GAD appears to be rather uniformly distributed throughout the cortical layers of the rat (112). In the monkey visual cortex, however, distinct laminar variations in GAD immunoreactivity are present, with the highest densities of GAD positive terminals in and around layer IV (51). Moreover, in the Macaca, within laminae I1 and I11 of area 17 some periodic variations in the density of GAD containing. cell bodies and terminals can be observed. This pattern of periodic dots (puffs) is identical with that shown for cytochrom oxidase and for 2-deoxyglucose (2DG) labeling. This suggests that the rows of GAD positive neurons in supragranular layers are preferentially related to each eye (50). The distribution of GABAergic neurons seems to correlate with the "puff" regions of elevated cytochrom oxidase activity also in the striate cortex of the squirrel monkey (19). In the kitten striate cortex GAD immunostaining associated with cells was found in all layers and was uniformly distributed in layers I1 to IV. In contrast, axon terminals positive for GAD immunostaining' showed laminar variations and formed a distinct band in layer IV. However, no evidence of dots in supragranular layers was reported (11). Important information about the possible site of GABA action derived from the examination of the distribution of GABA receptors. Our own studies (144) as well as the data of other authors (94, 128) show a distinct laminar pattern of [3H]muscimol - GABA agonist - binding in the visual cortex of young kittens and adult cats. The highest concentration of [3H]muscimol binding occurs in cortical layer IV. No evidence was found for periodicity in the pattern of distribution of binding sites within the laminar organization (92, 144), as was described by Hendrickson et al. (51) for GAD immunoreactivity. The GABA level itself varied 'gmong the cortical layers in the occipital cortex of, thq rat's brain, the highest being detected in layer IV (59). The pattern of distribution of GABAergic markers showing the highest concentration in layer IV suggests a strong influence of GABA on the terminals of thalamocortical afferents in the striate cortex and its passible role in shaping the properties of visual cortical neurons. The earliest evidence that GABA is the major inhibitory transmitter in the visual cortex from the results of Iversen, et al. (60), showing that GABA is released during inhibition in the cat's visual cortex in a calcium dependent way. Subsequently, Sillito and his coworkers demonstrated that GABA has a strong inhibitory effect on visual cortical neurons, which can be blocked by the GABA antagonist, bicuculline (133, 134). Moreover, GABA-mediated inhibitory mechanisms contribute to the visual response properties of neurons in the cat's visual cortex because the iontophoretic application of bicuculline reduces directional

and orientation selectivities and produces other modifications of the receptive field properies of cells (135). It has also been found that GABAmediated inhibition plays some role in determining O.D. (140). Electrophysiological studies revealed powerful GABAergic mechanisms operating in the visual cortex, which determine the receptive field properties and may dictate the actual responsiveness of cells to the visual input. These data together with the results concerning the presence and distribution of GABAergic markers in the striate cortex suggest a possible involvement of GABAergic transmission in the plastic changes of the properties of cortical neurons observed after manipulation of visual input during the critical period. Some inchcations concerning the possible participation of the GABAergic mechanism in cortical plasticity has been provided by ontogenetic studies. Despite the fact that GABAergic inhibition operates already in a group of neurons in the visual cortex of very young kittens (118, 167), intracortical GABAergic inhibition has not been fully established in the visual cortex until the end of the critical period for cortical modifiability. It appears that GAD activity develops relatively late and in the rat visual cortex remains very low at the time of eye opening (78, 85). The absolute and relative numbers of inhibitory synapses using GABA as a transmitter are much lower in the postnatal than in the mature cortex (166, 168). In the visual cortex of the cat the peak of [3H]muscimol binding density occurred at 3 months postnatally. In 3 days old kittens binding density was about 40°/o of the maximal value wkereas in adult cats it represented about 70°/c of the peak of binhng density (128). Moreover, the number of GABA binding sites is higher in cats after a long period of dark rearing than in normal cats (126). One of the most fully investigated phenomena of neuronal plasticity is the change of O.D. pattern following monocular deprivation. The mechanism underlying the effect of MD is still not clear. It has been suggested that MD results in the reduction of the efficiency of excitatory input in deprived pathways (139). Another explanation focusses on selective suppression on the deprived eye input by the GABA mediated inhibition exerted by connections from the open eye. The possibility of the involvement of inhibitory mechanisms in the O.D. shift derives from the following observations: (i) in MD kittens enucleation of the open eye restored responsiveness to the deprived eye in many cortical neurons. This effect was age related and, being most pronounced in 4-5 weeks old kittens, it still persisted in adult cats. Thus it appeared that the responses of the deprived eye were somehow being suppressed by the tonic activity of the normal eye (74); (ii) iontophoretically applied bicuculline restored binocularity in MD kittens (37). Therefore, when the inhibitory inputs are blocked by bicuculline, excitatory inputs are unma- . 6

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sked and the responses of neurons to the deprived eye stimulation are restored. In this case GABAergic inhibition seems to play an active role in the effects of MD. However, the effects of bicuculline could be given an explanation which speaks in favour of the mechanism involving the r.eduction of excitatory input in the deprived pathw'ay. If MD reduces the efficiency of the excitatory input with the inhibitory inputs unaffected, bicuculline makes it possible to reveal the weak cortical responsiveness to deprived pathway stimulation. Therefore in this case GABAergic inhibition seems to play only a passive role in the effect of MD (11). If the shift of O.D. towards the open eye is associated with an active role of GABAergic inhibition, one might expect to see differences in the level of the GABAergic markers and/or their distribution between normal and MD animals. Some indications concerning the alterations of the GABA system in the visual cortex as a result of abnormal visual experience were found in our studies of the effects of short monocular vision on GABA receptor binding activity in 5 weeks old kittens (145). Using [3H]muscimol as a ligand, we were able to show that 3 days of monocular vision resulted in an increase of GABA receptor binding in the striate cortex of both normally reared and binocularly deprived animals (by nearly 50°/a). BD since birth did not affect the GABA receptor binding. It should be stressed that neither 3 days of binocular vision in deprived kittens nor 3 days of binocular deprivation in normally reared ones produced significant changes in GABA receptor binding (145). The enhancement of [3H]muscimol binding observed after 3 days of monocular vision seems to be related to the increase of receptor affinity rather than to the change of the total number of receptor sites (146). Comparison of autoradiographic images generated from normal and MD kittens showed an increase of the [3H]muscimol label in the visual cortex area 17 in MD kittens confirming the biochemical results. However, no alterations in the laminar distribution of labeling was detected. We suggest that changes in the activation of the GABAergic system are specifically due to the asymmetric visual input and are probably connected with the mechanisms of O.D. shift. Surprisingly, Mower et al. (92) reported that long MD, lasting 8-12 months, did not affect the total number, affinity and regional distribution of the GABA receptor in the visual cortex a s revealed by the [3H]muscimol binding. Similarly, unilateral eyelid closure in the rat from the 11th to the 25th day did not affect the developmental pattern of GABA a receptor in the visual cortex (121). On the other hand, recent results of Shaw and Cynader (126) demonstrate that hlD from the time of eye opening results in an increase of the GABA

receptor number. This tends to support our suggesticxn about the role of GABA mediation in the mechanism of O.D. shift. From the results showing the increase of the [3H]muscimol binding activity after MD as well as from the results of bicuculline administration it seems reasonable to conclude that the GABA influence on the O.D. shift involved GABA, receptor sites. However, other GABA receptors can also be affected by MD. For instance GABA, receptor sites, bicuculline insensitive, are present in the striate cortex of the cat, because the iontophoretic application of baclofen inhibited the spontanous and visually evoked responses of neurons independently of the bicuculline action (7). Appart from the alteration of the receptor sites other changes in the GABA system as a result of MD are also possible. These include changes in the GABA containing neurons and terminals. In fact, Hendry and Jones (52) found that eye removal or MD reduce the number of immunocytochemically stained GABA and GAD somata and terminals in deprived-eye dominance columns in area 17 of the monkey. They interpreted this reduction a s being due to a decline in the GABA and GAD concentrations within the individual neurons and terminals to the point where the substances are no longer detectable by immunocytochemistry, since no reduction in the total neuronal density in area 17 was detected. The decline of GABA levels in cortical intrinsic neurons and axon terminals should produce changes in the physiological activity of their target cells. These changes could account for the functional expansion of the intact-eye dominated columns. These data seem to show a regulation of cortical transmitter levels by sensory experience. Interestingly, this effect was observed in adult monkeys 2 weeks after eye removal or 11 weeks after suturing the lid of one eye. In contrast, Bear and his coworkers (ll), using GAD immunocytochemistry as well as biochemical GAD assay, were unable to find changes in the distribution and activity of this enzyme in the striate costex in the monocularly enucleated or MD kittens. Both enucleation and MD have no consistent effects on either the regional or the laminar distribution of GAD in the striate cortex. The band of layer IV puncta remained uniform even though the periods of MD examined had been sufficient to cause a physiological O.D. shift in the striate cortex. These results led the authors to the conclusions that the numerical density of GABAergic synapses in the visual cortex is not regulated directly by thalamic activity and that changes in the density of GABAergic synapses do not account for the O.D. shift observed in the kitten striate cortex after MD. The data discussed imply that the results of experiments concerning the involvemznt of GABAergic system in visual cortical plasticity are

not univocal. The postulated key role of GABAergic mechanisms in adaptive changes (113) and in input selection and restriction (38) in the nervous system imply, however, the involvement of GABA meaated processes in visual cortical plasticity. ACETYLCHOLINE

Neuroanatomical studies show that in the striate cortex of the cat all cholinergic innervation arises entirely from extrinsic sources (8). Similarly, no evidence exists for the involvement of cholinergic transmission in the primary optic system of the rat (14, 163). Thus it seems that basal .forebrain nuclei are the sole source of cholinergic projection to the striate cortex and probably also to the subcortical visual centres. The studies in question employed acetylcholinesterase (AChE) histochemistry to investigate cholinergic innervation. Recently, using monoclonal antibodies directed against choline acetyltransferase (ChAT), Stichel et al. (155) have strenghened the earlier results showing that in the visual cortex (area 17) of the cat, despite dense cholinergic innervation only a few ChAT positive neurons can be detected. ChAT positive fibers and varicosities have been found t a be present in all layers of the Visual cortex. The distribution pattern of cholinergic fibers is compatible with the notion that ACh modulates cortical activity (152, 153). Although the direct cholinergic innervation of visual centers is lacking, iontophoretically applied ACh strongly affects the activity of visual neurons. In the striate cortex the responses of most neurons are modified byl ACh. ACh exerts a dual action on the specific responses of cells in area 17 of the cat. The responses of most cells are enhanced by ACh, Cells facilitated by ACh have been found in all cortical laminae, while those inhibited by ACh were found in laminae I11 and IV (138). Recent electrophysiological investigations also suggest a dual action of ACh in cat LGN : ACh blocked intrageniculate inhibition and exerted direct facilitation of relay cells (36). These observations speak in favour of the view that ACh acts as a modulator in visual information processing. Biochemical investigations of late 60ties and early 70ties indicated that keeping the animals in a modified visual environment can affect the level of AChE, a degradative enzyme for ACh (13, 21, 84). These observations may suggest the involvement of ACh transmission in modulating visual functions. Our biochemical results concerning the changes of AChE as well as ChAT activities in the visual areas of the cat's brain during development suggest the participation of cholinergic mechanisms in visual information processing (106). We have found that the ChAT activity rises from the cat's birth to reach the maximal level by

the 3rd month of its life and then drops to the adult level. In contrast, the developmental profile of AChE is quite different. The enzyme activity, reaching 90°/o of the adult value at 1 week of age, drops at the onset of the critical period and remains low until the third postnatal month. These results can be interpreted as an expression of enhanced availability of ACh during the critical period. Furthermore, BD from the 8th day of life, (the time of eye opening) apparently increases the activity of AChE in the cat's visual cortex and in LGN, but t h s ChAT activity remains unchanged in comparison with that observed in cats with normal binocular vision. Therefore it is plausible to maintain that the level of ACh is reduced in BD animals. Histochemical studtes have shown the pattern of developmental changes in AChE positive fibres and AChE positive cell bodies in the visual cortex of the cat. Namely, Bear et al. (9) observed that the development of AChE positive axons in the striate cortex is not fully complete until the age of at least 3 months, and is characterized by a number of distinct events. The most interesting phenomenon seems to be the appearance and position of AChE positive cell bodies. Stained cells first appear in the white matter subjacent to layer VI shortly after birth. After 2 weeks most cells in layer VI are also AChE positive. The staining of these cells gradually disappears over the next 2 months until, at the age of 3 months, there are no AChE positive cells in the cat's visual cortex. Some stained neurons are detected in layer V by the age of 1 year and persist throughout adulthood. Lately, reports showed that there were no indications of the striate cortex of the receiving an especially dense cholinergic input during the critical period (154). Comparison of our biochemical data with those found by using histochemistry clearly shows discrepancies between the results obtained. One of the possible explanations proposed by Stichel and Singer (154) is that biochemical investigations consider all forms of AChE whereas histochemical methods exclude the soluble forms of the enzyme. Laminar distribution of AChE activity shows some unexpected features. In adult mammals layer IV is poor in AChE activity (34). However, at least in the visual cortex of the rat, a transient AChE activity in layer IV appears during the period in which geniculocortical axon terminals are establishing functicmal connections with the postsynaptic sites in the cortex (115, 116). These data suggest that AChE may play a role in the development of neuronal connections, as has been suggested by Robertson (114). Thus the changes in AChE activity registered during development can be related to processes not exclusively connected with cholinergic mechanisms (48). Unilateral enucleation performed on the monkey c5anges the pattern

of distribution of AChE activity in the striate cortex Stripes of high AChE activity alternate regularly with zones of low AChE activity In layer IVc. Stripes of dark staining for AChE coincided with stripes of low cytochrom oxidase activity, clearly showing a relation to the O.D.. The reason of this response is unknown but this study shows that AChE activity in the visual cortex is dependent on the activity in the thalamo-cortical pathways (47, 50). i The function of ACh in the cerebral cortex appears to be largely mediated by muscarinic receptors (MChRs) (75). Biochemical and autoradiographic investigations have shown the presence of muscarinic binding sites in the visual cortex (24, 25, 117, 129). Our autoradiographic studies (144) have demonstrated the laminar variations in [3H]quinuclidinyl benzilate ([3H]QNB) binding in visual cortical areas in young kittens (5 weeks old). The weakest binding occurred in layer IV. Supragranular layers and layer V were strongly labelled. A similar pattern of distribution of muscarinic binding sites was found also in adult cats by using . [ ~ H ] Q N Bor N-[3H]methylscopolamine ([SHINMS) as a ligand (29). Among muscarinic binding sites both subclass M1 and subclass M2 are present. A comparison of the inhibition of the [3H]NMS binding by 100 pM carbachol and 300 nM pirenzepine showed that subcortical visual structures, e.g. LGN and superior colliculus, contain predominantly M2 sites. However, M1 sites constitute the main population of MChRs in the primary and accessory visual cortical areas but layer IV seems to be enriched in Mp sites. The predominance of Mz sites in the subcortical visual structures and the relatively higher proportion of these sites in cortical layer IV are compatible with the view that mainly M2 sites are involved in the modulation of synaptic activity at the primary stage of the visual information processing (29). Detailed ontogenetic studies of Shaw et al. (129) revealed striking changes in the distribution of MChRs in the striate cortex. In 3 days old kittens they found the highest [3B]QNB binding in layer IV. During development the pattern of binding reversed and by 3 months layer IV was the least densely labelled. Moreover, the biochemical data show that, especially during the critical period, changes in number and affinity of MChRs take place. The highest receptor sensitivity (expressed as the ratio Rs = Bmax: 2Kd) was observed after 6 weeks postnatally, then it decreased and achieved the adult levels in 3 months old kittens. The changes both in number and affinity may suggest a mechanism of controlling or enhancing the sensitivity of the postsynaptic response during development. Furthermore, the observation that the peak of receptor sensitivity occurs during the, critical period may suggest a possible functional role for this phenomenon in the plasticity process (130). The results of earlier stu-

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dies performed on rats also suggest the involvement of MChRs in modulating visual functions. An elevation of [3H]QNB binding level was found in dark reared rats within 3 hours of the onset of light exposure: however, the response was transient and by 24 h had disappeared (117). MD and dark rearing resulted in a reduction of [3H]QNB binding in the visual cortex of both hemispheres but an elevation in both superior colliculi in 25 days old rats. However, these effects disappeared completely in adult rats (119). Since the first visual stimulation and abnormal visual environment affect MChRs, it is reasonable to conclude that cholinergic muscarinic action may influence visual functions. Apart from muscarinic action, the possibility of cholinergic nicotinic transmission in modulating neuronal activity in the cat's visual areas should be taken carefully into consideration. Recently, the presence of [3H]nicotinic binding sites has been reported (100). These sites were located preferentially in layer IV of area 17. The conclusive results of Prusky et al. (107, 108) clearly show that nicotine receptors are located presynaptically on LGN terminals in the primary visual cortex of the cat. Thus nicotinic receptors-may play a specific function in regulating the activity of the primary visual thalamic input. To sum up, both muscarinic and nicotinic cholinergic receptors are present in the visual system. The different distribution of these receptor sites suggests that the action of ACh may depend on the precise cortical location at which the transmitter is released. The striking developmental characteristics of both the muscarinic and the nicotinic ACh receptors associated with the critical period for visual cortex plasticity suggest an important role for cholinergic systems in the alterations of the cortical function by the changed visual input (107). New information concerning the involvement of ACh in modulating visual cortical plasticity emerges from the results of Bear and Singer (12). They show that the combined destruction of the cortical noradrenergic and cholinergic innervations reduces the physiological response to MD although lesions of either system alone are ineffective. These data point to the possibility that ACh and NA facilitate synaptic modifications in the visual cortex by a common molecular mechanism (12, 140). It has been suggested that the removal of a sufficient amount of facilitatory extrageniculate input could lower cortical excitability below the threshold of synaptic modification and therefore block plasticity (12). The authors, however, did not exclude the possibility that the actions of NA nad ACh can regulate some events more specifically related to the control of synaptic plasticity, for example second messenger-dependent phosphorylation of proteins which are involved in the modification of synaptic properties. The changes in cholinergic markers during development and after

manipulation with visual input, and the combined effect of ACh and NA depletions on the O.D. plasticity give good reasons to believe that ACh is involved in the plastic modification of the properties of visual cortical neurons. Moreover, the new results of Metherate et al. (86), showing that iontophoretically administered ACh permits enhancement of neuronal responsiveness in the cat's primary somatosensory cortex, support the belief in the cholinergic influence on plastic phenomena. NORADRENALINE

Neurons containing noradrenaline which are located in the locus coei-uleus project widely and monosynaptically upon the cerebral cortex (71, 89, 158). The major noradrenergic fibres are oriented longitudinally through the grey matter and branch widely; thus NA can modulate neuronal activity synchronously throughout a vast area of the neocortex. Noradrenergic innervation of area 17 in primates exibits the most highly differentiated laminar pattern of all the neocortical areas (88). Layers V and VI appear to receive dense innervation whereas layer IV receives only a poor projection. The pattern of NA innervation and the fact that monoaminergic fibres form also conventional synapses in the cerebral cortex (98) suggest that NA action is directed at a specific set of visual cortical neurons, and therefore it seems that the action of NA is much more specific than has been suggested (158). On the other hand, the fact that NA fibres are very few in layer IVc (87, 88) seems to indicate that NA does not play a significant role in the modulation of the activity of geniculocortical terminals. The early ontogenetic appearance of the NA innervations and their tangential distribution pattern suggest a neurotrophic role (158). In 1976 Kasamatsu and Pettigrew (65) reported that 6-hydroxydopamine treatment prevents the O.D. shift produced by MD, and suggested that catecholamines may play an important role in the regulation of neuronal plasticity in the kitten visual cortex. The results of their subsequent studies, especially their discovery that microperfusion with NA resulted in restoration of cortical plasticity (66), seemed to support this suggestion and led to the hypothesis that NA input to the visual cortex is necessary to maintain plasticity (evidence reviewed by Kasamatsu, 64). But the results of other authors have failed to demonstrate the relationship between the cortical NA level and the ability of visual neurons to change their functional properties (1, 10, 32, 33). Nevertheless, there is general agreement that microperfusion of the visual cortex with 6-hydroxydopamine blocks plasticity during the critical period. Few data are available concerning the cortical distribution of NA

receptors. In rats P-adrenergic receptors are present in all layers but predominate in layers I-IV (96, 97), whereas a-receptors are uniformly distributed throughout the cortex in low concentration (169). In the visual cortex of the cat the density of P-adrenergic receptors has been found to be highest in the supragranular layers and lowest in layer IV (3). Also in the ferret visual cortex laminar variations in the distribution of al and PI-adrenoreceptors have been reported (45). The density of &-receptors has been found to be high over layers 1-11 and very low over layer IV, and intermediate over deep layers. In contrast, the areceptors are seen to be diffusely distributed, but preferentialy concentrated in layer IV and upper layers. The distribution of these receptor types may suggest two different ways for NA influence. The al-receptors may be preferentially associated with the enhancement of the excitatory input to layer IV, while the P1-receptors can be linked to the enhancement of inhibitory response outside layer IV. The high concentration of a, adrenoreceptors in layer IV, which coincides with the distribution of afferent terminals of the LGN in cats (80), and a periodic pattern of a,-receptors seen in cortical layer I11 imply that these receptors may be involved in the O.D. columns. The distribution of the 13-receptors suggest that these receptor sites act mainly in the supragranular layers and therefore may play a role in regulating secondary intracortical processing. To test the possible role of (3-adrenergic receptors in determining the state of developmental plasticity, the ontogeny of binding capacity in the visual cortex of the cat has been examined. Wilkinson et al. (165) found that in the visual cortex of the cat the binding of P-adrenergic ligand [3H] dihydroalprenolol ([SHIDHA) increases quickly from birth to 4 weeks, then rises slowly and reaches the maximum at 12 weeks. The adult pattern of the distribution of 0-adrenergic receptor sites is already formed at the beginning of the critical period (3). These re4 sults show that fl-adrenergic bindng site density increase coincides with the onset of the physiologically defined critical period and correlates with developmental profile of NA levels (62). Jonssbn and Kasamatsu, however, registered a different developmental pattern of P-adrenergic receptor sites (62). They observed a clear peak of [3H]DHA binding at the age of 7-9 weeks; then followed a decrease and at 11 weeks postnatally the adult level was reached. Such a maturation curve may indicate a correlation between the (I-adrenergic sites and the duration of the critical period. Lack of the effect of dark rearing and monocular eyelid suture on the developmental pattern in the visual cortex of kittens (3, 165) and rats (120) inhcates that the receptor sites are probably not involved directly in determining the state of plasticity that is seen du-

ring the critical period. But using pharmacological approach Shirokawa and Kasamatsu (132) were able to show the concentration dependent suppression by fl-adrenergic antagonists of the shift on O.D. following MD. These results were interpreted as suggesting that there is a positive correlation between the number of activated fl-adrenergic receptors within the visual cortex and the extent of changes in O.D. following MD (67, 68, 132). On the other hand, the comparison of the responses of visual cortical neurons during iontophoresis of NA showed no differences in the effects of NA observed between adult cats and kittens (162). NA involvement in visual'cortical plasticity is still disputed (compare 162) but, as mentioned in the section concerning ACh, it seems that the presence of both ACh and NA inputs is necessary for the plasticity of t h e visual cortex (12). SEROTONIN

Neurons containing serotonin (5-HT) which are located in midbrain raphe nuclei project widely and monosynaptically upon the cerebral cortex (71). The anatomical studies on primates have demonstrated that 5-HT axons are differentially distributed within the visual cortex and show a distinct laminar pattern of innervation (71, 88). Although some species differences exist, it has been found that layer IV receives very dense serotonergic projections. Since serotonergic innervation is directed to definite cortical layers, it seems that the action of this transmitter has a restricted role in cortical circuitry. Interestingly, in the squirrel monkey (New World monkey) complementary 5-HT and NA laminar innervation was observed, but in the macaque (Old World monkey) 5-HT and NA axons show a considerable overlap (87, 89). Nonetheless, the 5-HT projection has a markedly higher density in layer IV in both species as compared with other layers (71). Moreover, it seems that in the visual cortex 5-HT levels are higher than those of NA (46). The relationship between serotonergic terminals and the columiar organization of the primary visual cortex remains obscure. Hendrickson (50) reported that 5-HT is preferentially localized in the interdots zones of the macaque's visual cortex area 17, which correspond t a the regions of low'cytochrome oxidase activity. This result suggests some link between serotonergic innervation and O.D. columns. Other authors, however, have been unable to detect any periodicity in the tangential distribution of 5-HT fibre density (71). 5-HT was found to inhibit the visually evoked activity of the majority of cortical neurons. This effect is prolonged (110, 111). On the grounds of these data it has been postulated that serotonin has a modulatory role in the visual cortex.

The biochemical data show a higher concentration of endogenous 5-HT in the visual cortex of the monkey compared with the more anterior cortical areas (18, 111). However, such a pattern was not found in the cerebral cortex of the cat, where the frontal cortices showed much higher 5-HT concentration (44). The developmental studies performed by Jonsson and Kasamatsu (62) show that the 5-HT level in the visual cortex of kittens is relatively high at birth. It increases dramatically, peaking at 3-5 weeks with a value similar to the adult level, and then decreases between 5 and 7 weeks. Between 7 and 13 weeks the serotonin level is about 50-60°/o of the adult value. The distribution of 5-HT receptors was investigated by using receptor binding autoradiography. Both high affinity (5-HT1) and low affinit y (5-HT,) binding sites are present in the visual cortex (101-104). Some laminar variations in 5-HT1 receptor densities were found in the visual cortex of the rat, the internal laminae showing higher binding than the external ones (102). In yoqng kittens [3H]5-HT labelled intensively the layer 1/11 and V (143). In the human brain, in Brodman area 17, the highest 5-HT binding was found in layer IVcP (103). It was found that there are species differences in the distribution of 5-HT receptors. The presence of a significant concentration of 5-HT receptor sites in the visual cortex may suggest the involvement of these receptors in the control of visual information processing. The developmental pattern of 5-HT receptor binding sites also shows a distinct peak at the age of 4 weeks (62). At this time the value of the binding activity is more than three times the adult value. Afterwards the binding decreases gradually. The authors argue that their data imply that the 5-HT system itself is not directly involved in the regulation of the critical period for cortical plasticity, but it is possible that it induces or triggers off the onset of sensitivity. The highest level of endogenous 5-HT and the highest receptor binding may be a manifestation of some processes related to the completion of neuronal differentiation regulated by 5-HT (49). Some evidence concerning the involvement of 5-HT in visual functions derives from the study of the effect of visual deprivation and visual stimulation upon the level of serotonergic system markers. Enucleation has no significant effect on the concentration of 5-HT in the subcortical visual centres of the rat but, it decreases markedly the concentration of 5-HT in the occipital cortex. These results show that the cortical 5-HT system is more susceptible to enucleation than LGN and the superior colliculus. Monocular lid suture affects all the visual structure and increases the concentration of 5-HT in the occipital cortex in both hemispheres (79). No changes in 5-HT receptors were found in dark reared rats, suggesting that the development of the 5-HT innervation to the cortex is not criticaly dependent on the visual input. But,

if dark reared rats were exposed twlight for 3h, a significant increase in 5-HT binding was observed in the visual cortex and the motor cortex. This effect was transient and there was a return to normal level after 7 days. Since the increase of binding was found also in the motor cortex, it seems that the response of 5-HT receptors reflects a more general effect, probably related to the overall arousal of the animal (93). Nevertheless, when kittens deprived binocularly of pattern vision until the 28-th day of their life had their first monocular visual experience, changes of serotonin levels were observed in the visual cortex. Stimulation for 3h resulted in an increase of the 5-HT level, whereas after 14 h it produced a decrease. The effect was transient, no longer detectable after 75 h of stimulation (73). The observed fluctuations in 5-HT levels may reflect changes in the state of cortical metabolism. These data seem to indicate that there is no simple relationship between the first visual experience and the activation of the serotonergic system, but rather that 5-HT is involved in many comdex, dynamic processes occurring during the first hours of stimulation in the visual cortex. The involvement appears to be transient, possibly subsiding after the first plastic changes in connectivity have taken place. FINAL REMARKS

In this paper an attempt has been made to review our present-day knowledge of the possible involvement of different neurotransmitter systems in the plastic phenomena occurring in the visual cortex during the critical period. It has been shown that numerous transmitter systems are present in the visual cortex, and are probably affecting the visual functions. These neurotransmitter systems reveal a specific laminar pattern of innervation and also a clearly defined laminar distribution of their receptors (Table I). This may reflect the pattern of cortical circuitry connected with the visual information processing. Even dopamine, not included in the above results and often neglected because of its low concentration in the striate cortex, shows a very specific distribution1 of innervation mainly addressed to laminae VI (105). In investigating the problem of neurotransmitter involvement in visual cortical plasticity two main experimental approaches are followed. The first one attempts to examine whether experimentally induced changes in neurotransmitter systems affect the visual cortical plasticity. The second one attempts to find which properties in the neurotransmitter system components are confined to the critical period in the hope of answering the question what makes the visual cortex susceptible to modification of its connectivity.

.

TABLEI Laminar distribution of difierent neurotransmitter receptor sites in striate cortex of adult cat. APV, D-2-amino-5-phosphonovalerate; [3H] AMPA, [3H] amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid; [3Hl NMS, N-[3H]methyIscopolamine; [3H] QNB, [3H] quinuclidinyl benzilate; I3H] 5-HT, [3H] 5-hydroxytryptamine; ['251] ICYP, [lZ5I]iodocyanopindolol; [3H] DHA, [3H dihydroalprenolol; [3H] CHA, [3H] cyclohexyladenosine; [3H] NECA, [3H] 5-N-ethylcarboxamidoadenosine -

-

Receptor

Ligand

GABAA NMDA Quisqualate Muscarinic MI M,

3H muscimol 3H glutamatef APV 3H AMPA 3H NMS or 3H QNB pirenzepine carbachol

Nicotinic 5-HTI 0-adrenergic

3H nicotine 3H 5-HT l Z 5 I ICYP 3H DHA 3H CHA 3H NECA

adenosine Al

+ +

Laminae with the highest denisity of receptor sites IV I, 11, 111 I, 11, VI I, 11, I11 In all laminar proportion of MI sites is higher except layer IV IV I, 11, V I, 11, 111 (lowest in IV) I, 11, 111, VI I, 11, 111 (absent in layer IV) I, I1

References 94, 143 17 131 29, 129, 143

100, 107 143 3 2, 127 127

--

Using the first of the above experimental approaches, Kasamatsu and Pettigrew (66) constructed the attractive hypothesis that NA plays an essential role in visual cortical plasticity, This initiated a series of investigations designed to verify the above notion. However, their results are contradictory and the hypothesis has been strongly criticized (33). Recently, Bear and Singer (12) have reported that both NA and ACh inputs are necessary for plasticity. A critical overview of the results concerning the pharmacology of visual cortical plasticity was presented by Sillito (138), who conjectured that any procedure that severely disturbs the normal functioning of the cortex may block plasticity. Nevertheless, it seems that these studies provide some valuable information, especially if they are considered together with the results of the experiments employing the second experimental approach. This approach is directed towards investigating the developmental pattern of particular neurotransmitter system components in normally reared and visually deprived animals, special attention being paid to the critical period. Although the results of these experiments do not prove causality between the registered developmental changes and the plastic properties of the cortex, they strongly suggest that neurotransmitter receptors may be the sites of modifications through which the alterations of synaptic

TABLE11 Neurotransmitter receptors and visual cortical plasticity in the cat

Receptor

NMDA

B-adrenergic

Muscarinic

5-HTI A, adenosine

~odificationof properties during critical period

Effect of manipulation with visual input

Effect of application of receptors blockkers

ketamine preVents O.D. shift after M D (109) APV prevents O.D. shift after M D (69,70,141) bicuculline resPeak of sensitivity 3 days of asymat 9 weeks (128, metrical visual in- tores binocula130) put rises receptor rity in M D binding level ducats (37) ring the critical period (145) MD and D R rises receptor densities (126) M D has no effect on receptor densities (92) Peak of binding D R has no effect propranolol and at 7-9 weeks (62) on developmental sotalol supress profile (165) or on O.D. shift after Progressive increa- laminar distribuM D (67,68,132) se of binding up tion (3, 165) to 12 weeks; then the level remains constant (1 65) Peak of sensitivity Transient increase in binding after at 6 weeks (129, 130) D R ; at 30 days D R has no effect on distribution and number of receptors (29,31) Peak of binding at 4 weeks (62) Adult binding le- D R has no effect vel at 30 days on binding pattern

Peak of binding D R has no effect at 4 weeks (17) on developnlental Peak of effective- profile (17) ness during the critical period (159)

DR, dark rearing; MD, monocular deprivation; O.D., ocular dominance

Involvement in plastic phenomena postulated

strongly suggested

disputed

not directly involved

not directly involved not directly involved

connectivity can be achieved, as has been suggested by Changeux and Dachin (20) (see Table 11). Therefore it is not surprising that in mechanism underlying visual cortical plasticity the involvement of receptor alterations has been postulated (31, 124, 130, 131, 142). Cynader and Shaw (31) proposed a hypothesis showing how receptor alterations might be involved in binocular competition. They claimed that the asymmetry of the visual input as a result of MD causes the migration of the receptor sites o n the surface of the visual neuron towards the input from the open eye. A similar process has been suggested for the receptor sites of other neurotransmitters and neuromodulators, which may also influence the way in which the postsynaptic receptors of the primary visual afferents are reorganized. In consequence of this redistribution the nerve terminals from the deprived affereats lose the functional contact with the postsynaptic neuron. This model, however, does not explain why the adult cortex does not exhibit changes in cortical connectivity in response to MD. It seems therefore that the reorganization of connectivity achieved by the suggested receptor redistribution as a result of the changed visual input requires some additional conditions to produce permanent alterations. Ontogenetic studies suggest that NMDA receptolrs can act as med~ator in use dependent changes of neuronal response properties since the peak of their density in the visual cortex occurs during the critical period. Moreover, a block of thtse receptors prevents the O.D. shift normally seen after a period of MD (Table 11). NMDA receptors could also be involved in the consolidation of plastic changes as indicated b y experiments with ketamine (109). The observation that intact cholinergic and noradrenergic inputs are necessary to provoke the shift of O.D. after MD during the critical period (12) may suggest that the facilitatory action of these neuroltransmitters: on the visual cortical neurons can cause the rise of the response to an excitatory stimulus from the open eye above some critical threshold necessary to activate the NMDA receptors, and m consequence to produce permanent changes in the properties of the visual neurons (Fig. 4). The results reviewed imply, however, that not cmly the excitatory input but also the inhibitory input is somehow involved in O.D. plasticity. Our results show that the GABA receptor sites are preferentially localized in layer IV (Table I). They respond to the asymmetry of the visual input with an increase of binding activity. Together wlth providing the data showing that bicuculline administration restores binocularity in MD cats, they might indicate the involvement of these receptor sites in O.D. plasticity. Thus it seems reasonable to assume

that not only the imbalance of the excitatory input from the two eyes may be responsible for loss of binocularity but also the changed activity of the inhibitory inputs may play a role. Recently, Artola and Singer (5) have found that the induction of long-term potentiation (LTP) in the visual cortex of the rat requires both the activation of the NMDA receptors and the concorninant reduction of GABA inhibition. These data may indicate that in the visual cortex NMDA mediated processes are controled by GABAergic mechanisms. Interestingly, recent morphological studies of Einstein et al. (39) have demonstrated that part of the geExcltato~g Input

\Release of Glu/Asp from geniculocortical nerve endings

\

A cti vatton of postsyn~ptic non NMDA recepfors

Depo/o~izutionof visual neupons

NA and ACh

inputs

-------t

Facilitatwy

action Activation o f NMDA receptors

I

i

Plastic changes Fig. 4. Visual input evokes the release of excitatory neurotransmitter, presumably Glu/Asp from geniculocortical nerve endings, and activates non NMDA glutamatergic receptors. This causes depolarization of pastsynaptic membrane. With coactivation of excitatory input and NA and ACh modulatory inputs the postsynaptic membrane depolarization reaches a threshold for the activation of the NMDA receptors. The NMDA channel becomes permeable to calcium ions and long lasting changes in the efficacy of excitatory synapses can be induced.

niculate synapses in layer IV appear to be syrhmetrical, suggesting that they might be GABAergic. The authors assumed that both direct excitatory and inhibitory terminals. are important contributors to the receptive field properties of the visual cortex.

'

There are some suggestions that it is the intracortical synapses and not geniculocortical synapses that are the first to be functionally altered by the asymmetry of the visual input, since the changes in activation in the striate cortex are first visible outside layer IV as revealed by 2DG studies (72). At the moment, however, it is not possible to decide if the intracortical activity plays a primary role in O.D. plasticity. In recent years a good deal of information about the presence of neuropeptides in the visual cortex and their coexistence with classical neurotransmitters has become available (83, 89, 99, 151). The regulation of long lasting events by neuropeptides may be of general importance in plastic phenomena occurring in the visual cortex during the critical period. Especially the prolonged action of neuropeptides can be a possible basis for permanent changes of the properties of cortical neurons after an abnormal visual input. Long term modifications of the visual cortical neuron properties can be accomplished by the processes mediated by second messengers. There is more and more evidence that the activation of protein kinases is associated with a prolonged modification of neuronal excitability (63, 95). It seems therefore reasonable to expect some changes in the phosphorylation processes after manipulation with the visual input. Immunocytochemical studies of Hendry and Kennedy (53) show that MD in monkeys causes an increase in the concentration of calcium/calmodulin dependent kinase I1 within the deprived eye columns. It has been found that the rise in this kinase immunoreactivity does not simply reflect a generalized increase in the synthesis of regulatory proteins inr the deprived neurons, because staining for synapsin I, a substrate for this kinase, has been unaffected. These results seems to indicate that changing levels of activity in visual cortical neurons can alter their regulatory machinery. Aoki and Siekevitz (4) have investigated the developmental changes in cAMP stimulated phosphorylation of the cat's visual cortex proteins. They report that dark rearing (DR) causes in vivo an increase in cAMP dependent phosphorylation of microtubule-associated protein (MAP 2) whereas exposure to light of DR animals results i n a large decrease in phosphorylation of MAP 2. Since MAP 2 phosphorylation appears to play a crucial role in the &ssociation of cytoskeletal structure, the authors suggested, that following DR, the cytoskeletal structure is in a relatively uncross-linked flexible state. After visual stimulation, MAP 2 is present in vlsual neurons mostly in a deplhosphorylated state, and Aoki and Siekevitz (4) suggest that a cytoskeletal structure of the scaffolding for the dendrites may be forming. It seems that cAMP dependent phosphorylation and dephosphorylation of MAP-2 may be an important factor inducing plasticity during the critical period 7

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through its action on the dendritic cytoskeletal organization involving tubulin and actin. An increase in tubulin synthesis in .the visual cortex of DR rats after exposure to light during the critical period was reported by CronllyDillon and Perry (28). Then the present authors found (142, 147) that short monocular stimulation (for several hours or 3 days) of normal or binocularly deprived kittens produces an elevation of the tubulin level in the visual cortex. Since the effect is disrupted by later binocular visual stimulation, we suggested that it may be related to a shift of O.D. due to an asymmetric visual input. Thus it seems that the changed activity in the visual pathways can affect the neuronal cytoskeleton. Neurotransmitters activating specific receptors affect, directly or indirectly via second messenger systems, the metabolism of neurons, especially protein phosphorylation. In this way long-lasting changes in synaptic connectivity can be geneqated. It seems that during the critical period there exists a peculiar pattern of interactions between numerous neurotransmitters and neuromodulators. This, together with the presumable action of some trophic factors, may create the unique conditions, which enable the visual cortical neurons to change their properties a s a result of alterations of the visual input. REFERENCES 1. ALLEN, E. E., BLAKEMORE, L. J., TROMBLEY, P. Q. and GORDON, B. 1987. Effect of desmethylimipramine cm norepinepherine content and plasticity of kitten visual cortex. Brain Res. 401: 397-400. 2. AOKI, C. 1985. Development of the A 1 adenwine receptors in the visual cortex of cats, dark reared and normally reared. Dev. Brain Res. 22: 125133. 3. AOKI, C., KAUFMAN, D. and RAINBOW, T. C. 1986. The ontogeny of the

4.

5. 6. 7.

8.

laminar distribution of (3-adrenergic receptors in the visual cortex of cats normally reared and dark-reared. Dev. Brain Res. 27: 109-116. AOKI, C. and SIEKEVITZ, P. 1985. Ontogenetic changes in the cyclic 3',5'-monophosphate-stimutable phosphorylation of cat visual cortex proteins, particularly of microtubule-associated protein 2 (MAP 2); Effects of normal and dark rearing and of the exposure to light. J. Neurosci. 5: 2465-2483. ARTOLA, A. and SINGER, W. 1987. Long-term potentiation and NMDA receptors in rat visual cortex. Nature 330: 649-652. BAUGHMAN, R. W. and GILBERT, C. D. 1981. Aspartate and glutamate a s possible neurotransmitters in the visual cortex. J. Neurosci. 1: 427-439. BAUMFALK, U. and ALBUS, K. 1987. Baclofen inhibits the spontaneous and visually evoked responses of neurmes in the striate cortex of the cat. Neurosci. Lett. 75: 187-192. BEAR, M. F., CARNES, K. M. and EBNER, F. F. 1985. An investigation of ch?linergic circuitry in cat striate cortex using acetylcholinesterase histochemistry. J. Comp. Neurol. 234: 411-413.

-

9. BEAR, M. F., CARNES, K. M. and EBNER, F. F. 1985. Postnatal changes i n the distribution of acetylcholinesterase in kitten ,striate cortex. J. Comp. Neurol. 237: 519-532. 10. BEAR, M. F. and DANIELS, J. D. 1983. The plastic response to monocular deprivation persists in kitten visual cortex after chronic depletion of noradrenaline. J. Neurosci. 3: 407-416. 11. BEAR, M. F., SCHMECHEL, D. E. and EBNER, F. F. 1985. Glutamic acid decarboxylase i n the striate cortex of normal and monocularly deprived kittens. J. Neurosci. 5: 1262-11275. 12. BEAR, M. F. and SINGER, W. 1986. Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320: 172-176. 13. BENNETT, E. L., ROZENZWEIG, M. R., DIAMOND, M. C., MORIMOTO, H. and HERBERT, M. 1974. Effects of successive environmentis on brain measures. Physiol. Behav. 12: 621-631. 14. BIGL, V. and SCHOBER, W. 1977. Cholinergic transmission in subcortical and cortical visual centers of rats: No evidence for the involvement of primary optic system. Exp. Brain Res. 27: 211-219. 15. BLACK, J. B., ADLAR, J. E., DREYFUS, C. F., JONAKAIT, G. M., KATZ, D. M., LaGAMMA, E. F. and MARKEY, K. M. 1984. Neurotransmitter plasticity a t the molecular level. Science 225: 1266-1270. 16. BLAKEMORE, C. and Van SLYTERS, R. C. 1974. Reversal of the physiological effects of monocular deprivation in kittens: further evidence for a sensitive period. J. Physiol. 237: 195-216. 17. BODE-GREUEL, K. and SINGER, W. 1987. Developmental changes of APVsensitive [SHIglutamate binding sites in the visual cortex of kitten~sand adult cats. Neuroscience (Suppl.) 22: S 229 18. BROWN, R. M., CRANE, A. M. and GOLDMAN, P. S. 1979. Regional distribution of monoamines in the cerebral cortex and subcortical structures of the rhesus monkey: Concentrations and in vivo synthesis rates. Brain Res. 168: 133-150. 19. CARROLL, E. W. and WONG-RILEY, M. 1985. Correlation between cytochrom oxidase staining and the uptake and laminar distribution of tritiate aspartate, glutamate, y-aminobutyrate and glycine in the striate cortex of squirrel monkey. Neuroscience 15: 959-976. 20. CHANGEUX, J. P. and DACHIN, A. 1976. Selective stabilization of develo~ i n e ,synapses a s a mechanism for the specifitation of neuronal network. Nature 264: 2697-2704. 21. CHARKRABARTI, T., DIAS, P. D., ROYCHOWDHURY, D. and DAGINAWALE H. F. 1974. Effect of unilateral visual deprivation on the activities of acetylcholinesterase, cholinesterase and carbonic anhydrase of the optic lobe of the pigeon. J. Neurochem. 22: 865-867. 22. CLARK, R. M. and COLLINS, G. G. S. 1976. The release of endogenous amino acids from the rat visual cortex. J. Physiol. (Lond.) 262: 383-400. 23. CLINE, H. T., DEBSKI, E. and CONSTANTINE-PATON, M. 1987. NMDA receptor antagonist desegregates ocular dominance columns. Neuroscience (Suppl.) 22: S 216. 24. C O R m S , R. and PALACIOS J. M. 1986. Muscarinic cholinergic receptor subtypes i n the rat brain. Quantitative autoradiographic studies. Brain Res. 362: 227-238. 25: CORTfCS, R., PROBST, A. and PALACIOS, J. M. 1987. Quantitative light mic-

26. 27. 28.

29.

30.

31.

32.

33.

34.

35.

36.

37. 38.

39.

40.

roscopic autoradiographic localization of cholinergic muscarinic receptors , in the human brain: forebrain. Neuroscience 20: 65-107. COTMAN, C. W. and IVERSEN, L. L. 1987. Excitatory amino a,cids i n the brain - focus on NMDA receptosrs. Trends Neurosci. 10: 263-265. CRAGG, B. G. 1975. The development of synapses i n the kitten visual cortex during visual deprivation. Exp. Neurol. 46: 445-451. CRONLY-DILLON, J. and PERRY, G. W,. 1979. Effect of visual experience on tubulin synthesis during a critical period of visual cortex development in the hooded rat. J. Physiol. (Lond.) 293: 469-484. CYMERMAN, U., PALACIOS, J. M., C O R m S , R. and SKANGIEL-KRAMSKA, J. 1987. Autorad~iographi'clocalization of muscarinic cholinergic receptors in visual areas of cat brain: variations i n sensitivity of N [3Hjmethylscopolamine biind4ing sites to carbachol and pirenzepine. Neurosci. Lett. 81: 13-18. CYNADER, M. and MITCHELL, D. E. 1980. Period of susceptibility of kitten visual cortex to the effect of monocular deprivatio'n extends beyond six months of age. Brain Res. 91. 545-550. CYNADER, M. and SHAW, C,. 1986. Mechanisms underlying developmental alterations of cortical ocular dominance. I n E. L. Keller and D. Zee (ed.), Adaptive processes i n visual and oculomotor systems. Pergamon Press, Oxford, p. 53-61. DAW, N. W., VIDEEN, T. O,., PARKINSON, D. and RADER, R. K. 1985. DSP-4(N-(2-chlorwthyl)-N-ethyl-2-bromobenzylamine)depletes noradrenaline i n kitten visual cortex without altering the effects of monocular deprivation. J. Neurosci. 5: 1925-1933. DAW, N. W., VIDEEN, T. O., ROBERTSON, T. W,. and RADER, R. K. 1985. An evaluation of the hypothesis that noradrenaliine affects plasticity in the developing visual cortex. In A. Fein and J. S. Levine (ed.), The visual system. Liss, New York, p. 133-144. DEAN,' A. F., BUNCH, S. T., TOLHURST, D. J. and LEWIS, P. R. 1982. The distribution of acetylcholinesterase i n the lateral geniculate nucleus of the cat and monkey. Brain Res. 244: 123-134. DeFELIPE, J. and JONES, E. G. 1985. Vertical organization of y-aminobutyric acid-accumulating intrinsic neuronal systems in monkey cerebral cortex. J. Neurosci. 5: 3246-3260. De LIMA, A. D., MONTERO, IV. M. and SINGER, W. 1985. The cholinergic innervation of the visual thalamus: a n EM immunocytochemical study. Exp. Brain Res. 59: 206-212. DUFFY, F,. H., SNODGRASS, S. R. and BURCHFIEL, J. L. 1976. Bicuculline reversal of deprivation amblyopia i n the cat. Nature 260: 256-257. DYKES, R. W., LANDRY, P., METHERATE, R. and HICKS, T. P. 1984. Functional role of GABA i n cat primary somatosensory cortex: shaping receptive fields of cortical neurons. J. Neurophysiol. 52: 1066-1093. EINSTEIN, G., DAVIS, T. L. and STERLING, P. 1987. Ultrastructure of synapse from t h e A-laminae of the lateral geniculate nucleus in layer IV of the cat striate cortex. J. Comp. Neurol. 260: 63-75. FOSSE, V. M. and FONNUM, F. 1987. Biochemical evidence for glutamate and/or aspartate as neurotransmitters i n fibers from the visual cortex to the lateral posterior thalamic nucleus (pulvinar) in rats. Brain Res. 400: 219-224.

FOSSE, V. M., HEGGELUND, P., IVERSEN, E. and FONNUM, F. 1984. Effects of area 17 ablation in neurotransmitter parameters in efferents to area 18, the lateral geniculate body, pulvinar and superior colliculus in the cat. Neurosci. Lett. 52: 323-328. GABBOTT, P. L. A. and SOMOGYI, I. 1986. Quantitative distribution of GABA-immunoreactive neurons i n the cat visual cortex (area 17) of t h e cat. Exp. Brain Res. 61: 311-323. GAREY, L. J. and PETTIGREW, D. J. 1974. Ultrastructural changes in kitten visual cortex after environmental modification. Brain Res. 66: 165-172. GAUDIN-CHAZAL, G., DASZUTA, A., FAUDON, M. and TERNAUX, J . P. 1979. 5-HT concentration in cats brain. Brain Res. 160: 281-293. GOFFINET, A. and ROCKLAND, K. S. 1985. Laminar distribution of al-and 8,-adrenoceptors in ferret visual cortex. Brain Res. 333: 11-17. GOLDMAN-RAKIC, P. S. and BROWN, R. M. 1982. Postnatal development of monoamine eontent and synthesis in the cerebral cortex of Rhesus monkey. Dev. B r a ~ nRes. 4: 339-349. GRAYBIEL, A. M. and RAGSDALE Jr., C. W. 1982. Pseudocholinesterase staining in primary visual pathway of the macaque monkey. Nature 299: 439-442. GREENFIELD, S. 1984. Acetylcholinesterase may have novel functions in the braln. Trends Neurosci. 7: 364-3M. HAYDON, P. G., McCOBB, D. P. and KATER, S. B. 1987. The regulation of neurite outgrowth, growth cone motility, and electrical synaptogenesis by seroton~n.J. Neurobiol. 18: 197-215. HENDRICKSON, A. 1985. Dots, stripes and columns in monkey visual cortex. Trends Neurosci. 8: 406-410. HENDRICKSON, A. E., HUNT, S. P. and WU, J. Y. 1981. Immunocytochemical localization of glutamic acid decarboxylase in monkey striate cortex. Nature 292: 605-607. HENDRY, S. H. C. and JONES, E. G. 1986. Reduction i n number of immunostained GABAergic neurones in deprived-eye dominance colums of monkey area-17. Nature 320: 750-753. HENDRY, S. H. C. and KENNEDY, M. B. 1986. Immunoreactivity for a calmodulin-dependent protein kinase is selectively increased i n macaque striate cortex after monocular deprivation. Proc. Natl. Acad. Sci. USA 83: 1536-1540. HESS, R. and MURATA, K. 1974. Effects of glutamate and GABA on specific response of neurones i n the visual cortex. Exp. Brain Res. 21: 285-297. HICKS, T. P., RUWE, W. D., VEALE, W. L. and VEENHUIZEN, J. 1987. Aspartate and glutamate as synaptic transmitters of parallel visual cortical pathways. Exp. Brain Res. 58: 421-425. HOCKFIELD, S., McKAY, R. D., HENDRY, S. H. C. and JONES, E. G. 1983. A surface antigen that identifies mular dominance columns in the visual cortex and laminar features of the lateral geniculate nucleus. Cold Spring Harbor Symposia on quantitative Biology, Vol. XLVIII; Molecular Neurobiology, Cold Spring Harbor Laboratory, p. 877-889. HOUSER, C. R., VAUGHM, J. E., HENDRY, S. H. C., JONES, E. G. and PETERS, A. 1984. GABA neurons in the cerebral cortex. In E. G. Jones and A. Peters (ed.), Cerebral cortex. Plenum Press, New York, Vol. 2,

I

58. HUBEL, D. H. and WIESEL, T. N. 1980. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J. Physiol. (Lond.) 206: 419-436. 59. ISHIKAWA, K., WATABE, S. and GOTO, N. 1983. Lamina1 distribution of y-aminobutyric acid (GABA) in the occipital cortex of rats: evidence as a neurotransmitter. Brain Res. 277: 361-364. 60. IVERSEN, L. L., MITCHELL, J. F. and SRINIVASAN, V. 1971. The release of y-amino-butyric acid during inhibition in the cat visual cortex. J. Physiol. (Lond.) 212: 519-534. 61. JASPER, H. H. and KOYAMA, I. 1969. Rate of release of amino acids from the cerebral cortex is affected by brainstem-thalamic stimulation. C a n J. Physiol. Pharmacol. 47: 889-905. 62. JONSSON, G. and KASAMATSU, T. 1983. Maturation of monoamine neurotransmitters and receptors in cat occipital cortex during postnatal critical period. Exp. Brain Res. 50: 449-458. 63. KACZMAREK, L. K., STRONG, J. A, and KAUER, J . A. 1986. The role of protein kinases in the control of prolonged changes in neuronal excitability. Prog. Brain Res. 69: 77-106. 64. KASAMATSU, T. 1983. Neuronal plasticity maintained by the central norepinephrine system in the cat visual cortex. Prog. Psychobiol. Physiol. Psychol. 10: 1-111. 65. KASAMATSU, T. and PETTIGREW, J. D. 1976. Depletion of brain catecholarnines: failure of ocular dominance shift after monocular occlusion i n kittens. Science 194: 206-209. 66. KASAMATSU, T., PETTIGREW, J. and ARY, M. 1979. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J. Comp. Neurol. 185: 163-182. 67. KASAMATSU, T. and SHIROKAWA, T. 1985. Involvement of 0-adrenorecep-8 tors in the shift of ocular dominance after monocular deprivation. Exp. Brain Res. 59: 507-514. 68. KASAMATSU, T, and SHIROKAWA, T. 1985. Are Beta adrenoreceptors involved in vlsuocortical plasticity? In B. E. Will, P. Schmitt and J. C. Dalrymple-Alford (ed.), Brain plasticity, learning, and memory. Plenum FUblishing Co., p. 79-84. 69. KLEINSCHMIDT, A., BEAR, M. F. and SINGER, W. 1986. Effects of thei NMDA receptor antagonist APV on visual cortical plasticity in monocularly deprived kittens. Neurosci. Lett. Suppl. 26: S58. 70. KLEINSCHMIDT, A., BEAR, M. F. and SINGER, W. 1987. Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238: 355-358. 71. KOSOFSKY, B. E., MOLLIVER, M. E., MORRISON, J. H. and FOOTE, S. L. 1984. The serotonin and norepinephrine innervation of primary visual cortex in the cynomolgus monkey (Macaca fascicullaris). J. Comp. Neurol. 230: 168-178. 72. KOSSUT, M., THOMPSON, I. D. and BLAKEMORE, C. 1983. Ocular dominance columns in cat striate cortex and effects of monocular deprivation: A 2-deoxy-glucose study. Acta Neurobiol. Exp. 43: 273-282. 73. KOSSUT, M., WOJCIK, M. and SKANGIEL-KRAMSKA, J. 1981. Dynamic changes of serotonin levels during the first visual experience in binocularly deprived kittens. J. Neurochem. 37: 1077-1080.

74. KRATZ, K. E.7 SPEAR, D. and SMITH, D. C. 1976. Postcritical period reversal of effects of mOn0~ular deprivation on striate cortex cells i n the cat. J . Neurophysiol. 39: 501-511. 75. KRNJEVIC, K. 1984. Neurotransmitter i n cerebral cortex a general account. In E. J. Jones and A. Peters (ed.), Cerebral cortex. Vol. 2. Pergamon Press, New York, p. 39-61. 76. KUPFER, C. and PALMER, P. 1984. Lateral geniculate nucleus, histological and cytochemical changes following afferent denervation and visual deprivation. Exp. Neurol. 9: 400-409. 77. KVALE, I. and FONNUM, F. 1983. The effects of unilateral neonatal of visual cortex on transmitter parameters in the adult superior colliculus and lateral geniculate body. Dev. Brain Res. 11: 261-266. 78. KVALE, I., FOSSE, V. M. and FONNUM, F. 1983. Development of neurotransmitter parameters i n lateral geniculate body, superior colliculus and visual cortex of t h e albino rat. Dev. Brain Res. 7: 137-145. 79. LAI, H., MAKOUS,'w. L., QUOCK, R. H. and HORITA, A. 1978. Visual deprivation affects serotonin levels in the visual system. J. Neurochem. 30: 1187-1189. 80. Le VAY, S. and GILBERT, C. D. 1976. Laminar patterns of geniculo-cortical projection in the cat. Brain Res. 113: 1-19. 81. Le VAY, S., STRYKER, M. P. and SHATZ, C. J. 1978. Ocular dominance column and their development i n layer IV of the cat's visual cortex: a quantitative study. J. Comp. Neurol. 179: 223-244. , 82. Le VAY, S., HUBEL, D. H. and WIESEL, ?]. N. 1975. The pattern of ocular dominance columns in macaque visual cortex revealed by reduced silver stain. J. Comp. Neurol. 159: 559-576. 83. LIN, C. S,, LU, S. M. and SCHMECHEL, D. E. 1986. Glutamic acid decarboxylase and somatostatin immunorad~oactivityin rat visual cortex. J. Comp. Neurol. 244: 369-383. 84. MALETTA, G. J. and TIMIRAS, P. S. 1967. Acetylcholinesterase activity i n optic structures after complete light deprivation from birth. Exp. Neurol. 19: 513-518. 83. McDONALD, J. K., SPECIALE, S. G. and PARNAVELAS, J. G. 1981. The development of glutamate decarboxylase i n the visual cortex and the dorsal lateral geniculate nucleus of the rat. Brain Res. 217: 364-367. 86. METHERATE, R., TREMBLAY, N. and DYKES, R. W. 1987. Acetylcholine permits long-term enhancement of neuronal responsiveness in cat primary somatosensory cortex. Neuroscience 22: 75-81. 87. MORRISON, J. H. and FOOTE, S. L. 1986. Noradrenergic and serotonergic innervation of cortical, thalamic and tectal visual structures in Old and New World monkeys. J. Comp. Neurol. 243: 117-138. 8& MORRISON, J. H., FOOTE, S. L., MOLLIVER, M. E., BLOOM, F. E,. and LIDOV, H. G. W. 1982. Noradrenergic and serotonergic fibers innervate complementary layers in monkey primary visual cortex: An immunohistochemical study. Proc. Natl. Acad. Sci. USA 79: 2401-2405. 89. MORRISON, J. H. and MAGISTRETTI, P. J . 1983. ~ o n o a m i n e sand peptldes in cerebral cortex-contrasting principles of cortical organization. rends Neurosci 6: 146-151. 90. MOWER, G. D., BERRY, D., BURCHF'IELD, J. L. and DUFFY, F. H. 1981. Comparison of the effects of dark-rearing and binocular suture on development and plasticity of cat visual cortex. Brain Res. 220: 255-267.

91. MOWER, G. D., CHRISTEN, W. G. and CAPLAN, C. J. 1983. Very brief visual experience eliminates plasticity in the cat visual cortex. Science 221: 178180. 92. MOWER, G. D., WHITE, W. F. and RUSTAD, R,. 1986. [3H] ~ u s c i m o lMnding of GABA receptors in the visual cortex of normal and monocularly deprived cats. Brain Res. 380: 253-260. 93. MURPHY, S., UZBEKOV, M. G. and ROSE, S. P. R. 1980. Changes i n serotonin receptors in different regions after light exposure of dark-reared rats. Neurosci. Lett. 17: 317-321. 94. NEEDLER, M. C., SHAW, C. and CYNADER, M. 1984. Characteristics and distribution of muscimol binding sites in c a t visual cortex. Brain Res. 308: 347-353. 95. NESTLER, E. J., WALAAS, S. I. a n d GREENGARD, P. 1984. Neuronal phosphoproteins: physiological and clinical implications. Science 225: 1337-1364. 96. PALACIOS, J. M. a n d KUHAR, M. J. 1980. Beta-adrenergic receptor localization by light microscopic autoradiography. Science 208: 1378-1380. 97. PALACIOS, J. M. and KUHAR, M. J. 1982. Beta-adrenergic receptor localization i n r a t brain by light microscopic autoradiography. Neurochem. Int. 4: 473-490. 98. PAPADOPOULOS, G. C., PARNAVELAS, J . G. and BUIJS, R. 1987. Monoaminergic fibers form conventional synapses in the cerebral cortex. Neurosci. Lett. 76: 275-279. 99. PAPADOPOULOS, G. C., PARNAVELAS, J. G. and COVANAGH, M. E. 1987. Extensive co-existence of neuropeptides i n t h e r a t visual cortex. Brain Res. 420: 95-100. 100. PARKINSON, D. and DAW, N. W. 1986. [3H]-Nicotine binding in cat visual cortex and receptor autoradiography. Soc. Neurosci. (Abstr.) 12: 582. 101. PAZOS, A., C O R T S , R. and PALACIOS, J . M. 1985. Quantitative autoradiographic mapping of serotonin receptors in the r a t brain. 11. Serotonin-2 receptors. Brain Res. 346: 231-249. 102. PAZOS, A. and PALACIOS, J . M. 1985. Quantitative autoradiographic mapping of serotonin receptors in the r a t brain. I. Serotonin-1 receptors. Brain Res. 346: 205-230. 103. PAZOS, A., PROBST, A. and PALACIQS, J. M. 1987. Serotonin receptors in the human brain - 111. Autoradiographic mapping of serotonin-1 receptors. Neuroscience 21: 97-122. 104. PAZOS, A,, PROBST, A. and PALACIOS, J. M. 1987. Serotonin receptors i n the human brain - IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21: 123-139. 105. PHILIPSON, 0. T., KILPATRICK, I. C. and JONES, M. W. 1987. Dopaminergic innervation of the primary visual cortex in the rat, a n d some correlations with human cortex. Brain Res. Bull. 18: 621-633. 106. POTEMPSKA, A., SKANGIEL-KRAMSKA, J. a n d KOSSUT, M. 1979. Development of cholinergic enzymes and adenosine-triphosphate activity of optic system of cats in normal and restricted visual input conditions. Dev. 107. PRUSKY, G. and CYNADER, M. 1986. The distributions of nicotinic a n d muscarinic acetylcholine binding sites in the developing cat visual cortex. Soc. Neurosci. (Abstr.) 12: 1372. 108. PRUSKY, G. T., SHAW, C. and CYNADER, M. S. 1987. Nicotine receptors

are located a n lateral geniculate nucleus terminals i n cat visual cortex. Brain Res. 412: 131-138. RAUSCHECKER, J. P. and HAHN, S. 1987. Ketamine-xylazine anaesthesia blocks consolidation of ocular dominance changes i n kitten visual cortex. Nature 326: 183-185. READER, T. A. 1978. The effect of dopamine, noradrenaline and serotonin in the visual cortex of the cat. Experientia 34: 1586-1587. READER, 'T. A., FERRON, A,, DESCARRIES, L. and JASPER, H. H. 1979. Modulatory role for biogenic amines in the cerebral cortex. Micro-iontophoretic studies. Brain Res. 160: 217-229. . RIBAK, C. E. 1978. Aspinous and sparsly-spinlous stellate neurons in the visual cortex of rats contain glutamic acid decarboxylase. J. Neurocytol. 7: 461-478. ROBERTS, J. 1986. What do GABA neurons really do? They make possible variability generation in relation to demand. Exp. Neurol. 93: 279-290. ROBERTSON, R. T. 1987. A morphogenic role for transiently expressed acetylcholinesterase i n developing thalamocortical systems? Neurosci. Lett. 75: 259-264. ROBERTSON, R. T., FOGOLIN, R. P., TIJERINA, A. A. and YU, J. 1987. Effects of neonatal monocular and binocular enucleation on transient acetylcholinesterase activity in developing rat visual cortex. Dev. Brain Res. 33: 185-187. ROBERTSON, R. T., TIJERINA, A. A. and GALLIVAN, M. E. 1985. Transient patterns of acetylcholinesterase activity in visual cortex of the rat: normal development and the effects of neonatal enucleation. Dev. Brain Res. 21: 203-214. ROSE, S. P. R. and STEWART, M. G. 1978. Transient increase in muscarinic acetylcholine receptor and acetylcholinesterase in visual cortex on first exposure of dark-reared rats to light. Nature 271: 169-170. SATO, H. and TSUMOTO, T. 1984. GABAergic inhibition already operates o n a grsoup of neurons i n the kitten visual cortex a t the time of eye opening. Dev. Brain Res. 12: 311-315. SCHLIEBS, R., BIGL, V. and BIESOLD, D. 1982. Development of muscarinic cholinergic receptor binding in the visual system of monocularly deprived dark reared rats. Neurochem. Res. 7: 1181-1197. SCHLIEBS, R., BURGOYNE, R. D. and BIGL, V. 1982. The effect of$ visual deprivation on 6-adrenergic receptors in the visual centres of the rat. J. Neurochem. 38: 1038-1043. SCHLIEBS, R. W. and ROTHE, T. 1987. Development of GABA A receptors i n the central visual structures of rat brain. Effect of visual pattern deprivation. Neuroscience (Suppl.) 22: S 235. SHATZ;C. J., LINDSTROM, S., and WIESEL, T. N. 1977. The distribution of afferents representing the right and left eyes in the cat's visual cortex. Brain Res. 39: 41-48. SHATZ, C. J., and STRYKER, M. P. 1978. Ocular dominance in layer I V of the cat's visual cortex and the effect of monocular deprivation. J. Physiol. (Lond.) 281: 267-283. SHAW, C., AOKI, C., NEEDLER, M. C., WILKINSON, M. and CYNADER, M. 1983. Ontogenesis of 6-adrenergic, GABA and benzodiazepine receptor binding sites i n cat visual colltex and the effects of dark rearing, In Abstracts of 3rd Capo Boi Conference on Neuroscience. The cell biology of

-

neuranal plasticity. Capo Boi Hotel Villasimius, Sardinia, Italy, p. 283-284. 125. SHAW, C. and CYNADER, M. 1984. Disruption of cortical activity prevents ocular dominance changes in monocularly deprived kittens. Nature 308: 731-734. 126. SHAW, C. and CYNADER, M. 1987. Increase i n GABAA receptor number in cat visual cortex after early visual deprivabon. Neuroscience (Suppl.) 22: S 289. 127. SHAW, C., HALL, S. and CYNADER, M. 1986. Characterization, distribu-

tion and ontogenesis of adenosine binding sites in cat visual cortex. J. Neurosni. 6: 3218-3228. 128. SHAW, C., NEEDUR, M. C. and CYNADER, M. 1984. Ontogenesis of muscimol binding sites in cat visual cortex. Brain Res. Bull. 13: 331-334. 129. SHAW, C., NEEDLER, M. C. and CYNADER, M. 1984. Ontogenesis of muscarinic acetylcholine binding sites in cat v,isual cortex: Reversal of specific laminar distribution duning critical period. Dev. Brain Res. 14: 285299. 130. SHAW, C., NEEDLER, M. C., WILKINSON, M., AOKI, C. and CYNADER, M. 1985. Modification of neurotransmitter receptor sensitivity in cat visual cortex during the critical period. Dev. Brain Res. 22: 67-73. 131. SHAW, C., WILKINSON, M., CYNADER, M., NEEDLER, M. C., AOKI, C. and HALL, E E. 1986. The laminar distribution and postnatal development

of neurotransmitter and neuromodulator receptors in cat yisual cortex. Brain Res. Bull. 16: 661-671. 132. SHIROKAWA, T. and KASAMATSU, T. 1986. Concentration-dependent supression by 0-adrenergic antagonists of the shift in ocular dominance following monocular deprivation in kitten visual cortex. Neuroscience 18: 1035-1046. 133. SILLITO, A. M. 1975. The contribution of inhibitory mechanism to the recep-

tive field properties of neurones in the striate cortex of the cat. J. Physiol. (Lond.) 250: 305-329. 134. SILLITO, E. 1975. The effectiveness of bicuculline as an antagonist of GABA and visually evoked inhibition in the cat's striate cortex. J. Physiol. (Lond.) 250: 287-304. 135. SILLITO, A. M. 1984. Functional considerations of the operation of GABAergic inhibitory processes in the visual cortex. In E. G. Jones and A. Peters (ed.), Cerebral cortex. Vol. 2. Plenum Press, New York, p. 91-117. 136. SILLITO, A. M. 1986. Cholinergic input and plasticity. Nature 320: 109-110. 137. SILLITO, A. M. 1986. Conflicts in the pharmacology of visual cortical plasticity. Trends Neurosci. 9: 301-303. 138. SILLITO, A. M. and KEMP, S. A. 1983. Cholinergic modulation of the functional organization of the cat visual cortex. Brain Res. 289: 143-155. 139. SILLITO, A. M., KEMP, J. A. and BLAKEMORE, C. 1981. The role of

GABAergic inhibition in the cortical effects of monocular deprivation. Nature 291: 218-320. 140. SILLITO, A. M., KEMP, J. A. and PATEL, H. 1980. Inhibitory interactions contributing to the ocular dominance of monocularly dominated cells in the normal cat striate cortex. Exp. Brain Res. 41: 1-10. 141. SINGER, W., KLEINSCHMIDT, A. and BEAR, M. F. 1986. ~nfusion of a n NMDA receptor antagonist disrupts ocular dominance plasticity in kitten striate cortex. Soc. Neurosci. (Abstr.) 12: 786.

SKANGIEL-KRAMSKA, J. 1980. Biochemical approach to the studies on plasticity of cerebral cortex of visually deprived cats. In M. Brzin, D. Sket and H. Bachelard (ed.), Synaptic constituents in health a n d disease. Mladinska Knjiga-Pergamon Press, Ljubljana, Oxford p. 353-378. SKANGIEL-KRAMSKA, J., CYMERMAN, U. and KOSSUT, M. 1985. Distribution of GABA, serotonin and muscarinic receptors in visual structures of kitten brain. Neurosci. Lett. (Suppl.) 22: S 384. SKANGIEL-KRAMSKA, J., CYMERMAN, U. and KOSSUT, M. 1986. Autoradiografic localization of GABAergic and muscarinic cholinergic receptor sites in t h e visual system of the kitten. Acta Neurobiol. Exp. 46: 119-130. SKANGIEL-KRAMSKA, J. and KOSSUT, M. 1984. Increase of GABA receptor binding activity after short lasting monocular deprivation in kittens. Acta Neurobiol. Exp. 44: 33-39. SKANGIEL-KRAMSKA, J. and KOSSUT, M. 1985. Monocular deprivation affects GABA receptor i n the visual cortex of kittens. Physiol. Bohemoslov. 34: 145-147. SKANGIEL-KRAMSKA, J., KOSSUT, M. and POTEMPSKA, A. 1983. Monocular stimulation induces tubulin response in the kittens visual cortex. In Abstracts of 3rd Capo Boi Conference on Neuroscience. The cell biology of neuronal plasticity. Capo Boi Hotel Villasimius, Sardinia, Italy, p. 285. SOLNICK, B., DAVIS, T. L. and STERLING, P. 1984. Numbers of specific types of neurons in layer IV a b of cat striate cortex. Proc. Natl. Acad. Sci. USA 81: 3898-3900. SOMOGYI, P.; COWEY, A,, HALASZ, N. and FREUND, T. F. 1981. Vertical organization of neurones accumulating 3H-GABA in visual cortex of rhesus monkey. Nature 294: 761-763. SOMOGYI, P., FREUND, T. W., WU, J. Y. and SMITH, A. D. 1983. The section-Golgi impregnation procedure. 2. Immunocytochemical demonstration of glutamate deca~boxylase in Golgi-impregnated neurons and their afferent synaptic boutms in the visual cortex of the cat. Neuroscience 9: 475-490. SOMOGYI, P., HODGSON, A. J., SMITH, A. D., NUNZI, M. G., GORIO, A. and WU, J. Y. 1984. Different populations of GABA-ergic neurons in the visual cortex and hippocampus olf cat contain somatostatin- or cholecystokinin-immunoreactive material. J. Neurosci. 4: 2590-2603; STICHEL, C. C., De LIMA, A. D. and SINGER, W. 1987. A search for choline acetyltransferase-like immunoreactivity in neurons of the cat striate cortex. Brain Res. 405: 395-399. STICHEL, C. C. and SINGER, W. 1985. Organization and m~orphologicalcharacteristics of choli~neacetyltransferase-containing fibres i n the visual thalamus and striate cortex of the cat. Neurosci. Lett. 53: 155-160. STICHEL, C. C. and SINGER, W. 1987. Quantitative analysis of the choline acetyltransferase-immunoreactive axonal network in the cat primary visual cortex: I. Adult cats. J. Com~p.Neurol. 258: 91-98. STICHEL, C. C. and SINGER, W. 1987. Quantitative analysis of the choline acetyltransferase-immunoreactive axonal network in the cat primary visual cortex: 11. Pre- and postnatal development. J. Comp. Neurol. 258: 99-111. THOMSON, A. M., WEST, D. C. and LODGE, D. 1985. An N-methylawpartate

157. 158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

receptor mediated synapse in r a t cerebral cortex: a site of action of ketamine? Nature 313: 479-481. TIEMAN, S. B. 1985. The anatomy of geniculocortical connections in monocularly deprived cats. Cell. Mol. Neurobiol. 5: 35-45. TIGGES, J. and TIGGES, M. 1985. Subcortical sources of direct projections to visual cortex. In A. Peters and E. G. Jones (ed.), Cerebral cortex. Plenum Press, New York, Vol. 3, p. 351-378. TSUMOTO, T., HAGIHARA, K., SATO, H. and HATA, Y. 1987. NMDA receptors i n the visual cortex of young kittens are more effective than those of adult cats. Nature 327: 513-514. TSUMOTO, T., MASUI, H, and SATO, H. 1986. Excitatory amino acid transmitters in neuronal circuits of t h e cat visual cortex. J. Neurophysiol. 55: 469-483. TURLEJSKI, K. and KOSSUT, M. 1985. Decrease in the number of synapses formed by subcortical inputs t o the striate cortex of binocularly deprived cats. Brain Res. 331: 115-125. VIDEEN, T. O.,DAW, N. W. and RADER, R. K. 1984. The effect of norepinephrine on visual cortical neurons in kittens and adult cats. J . Neurosci. 4: 1607-1617. WENK, H., BIGL, V. and MEYER, U. 1981. Ch'olinergic projections from magnocellular nuclei of the basal forebrain to cortical areas in rats. Brain Res. Rev. 2: 211-219. WIESEL, T. N. and HUBEL, D. H. 1963. Single-cell responses in the striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26: 10031017. WILKINSON, M., SHAW, C., KHAN, I. and CYNADER, M. 1983. Ontogenesis of 8-adrenergic binding sites in kitten visual cortex and t h e effects of visual deprivation. Dev. Brain Res. 7: 349-352. WINFIELD, D. A. 1983. The postnatal develo@ent of synapses in the different laminae of the visual cortex in the normal kitten and in kitten with eyelid closure. Dev. Brain Res. 9: 155-169. WOLF, W., HICKS, T. P. and ALBUS, K. 1986. The contribution of GABAmediated inhibitory mechanisms to visual response properties of neurons in the kitten's striate cortex. J . Neurosci. 6: 2779-2795. WOLFF, J. R., BOTTCHER, H., ZETZSCHE, T., OERTEL, W. H, and CHRONWALL, B. M. 1984. Development of GABAergic neurons in r a t visual cartex a s identified by glutamate decarboxylase-like immunoreactivity. Neurosci. Lett. 47: 207-212. YOUNG, W. S. and KUHAR, M. J. 1980. Noradrenergic alpha-1 a n d alpha-2 receptors: light microscopic localization. Proc. Natl. Acad. Sci. USA 77: 1696-1700.

Accepted 26 May 1988