Cell Tissue Res DOI 10.1007/s00441-006-0269-2
REVIEW
Synapses formed by normal and abnormal hippocampal mossy fibers Michael Frotscher & Peter Jonas & Robert S. Sloviter
Received: 15 May 2006 / Accepted: 31 May 2006 # Springer-Verlag 2006
Abstract The axon terminals (mossy fibers) of hippocampal dentate granule cells form characteristic synaptic connections with large spines or excrescences of both hilar mossy cells and CA3 pyramidal neurons. Interneurons of the hilar region and area CA3 are also prominent targets of mossy fibers. The tracing of biocytin-filled mossy fibers and immunolabeling of target cells with interneuron markers has revealed that the majority of mossy fiber synapses project to γ aminobutyric acid (GABA)-ergic inhibitory interneurons rather than to excitatory principal cells, although the functional implications of these quantitative differences are unclear. Following a brief description of the “classical” mossy fiber synapse on excrescences of CA3 pyramidal cells, the present review focuses on the contacts formed between granule cells and GABAergic interneurons, both normally and after synaptic reorganization. In response to deafferentation of mossy cell target cells, which include both granule cells and interneurons, mossy fibers “sprout” new axon collaterals that form a band of supragranular mossy The work at the authors’ laboratories is supported by the Deutsche Forschungsgemeinschaft (Transregio Sonderforschungsbereich TR-3, to M.F.), and NIH-NINDS (grant no. NS 18201, to R.S.S.). We thank Sigrun Nestel for excellent technical assistance. M. Frotscher (*) Institut für Anatomie und Zellbiologie und Zentrum für Neurowissenschaften, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany e-mail:
[email protected] P. Jonas Physiologisches Institut, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany R. S. Sloviter Departments of Pharmacology and Neurology, University of Arizona College of Medicine, Tucson, AZ 85724, USA
fibers in the inner molecular layer of the dentate gyrus. Although most newly formed recurrent mossy fibers establish synapses with granule cells, there is an apparently convergent input of new mossy fibers onto GABA-immunoreactive interneuron dendrites that traverse the inner molecular layer. These mossy fiber-interneuron synapses in the dentate gyrus are observed in chronically epileptic rats and may be the structural correlate of the granule cell hyperinhibition observed in these animals in vivo. Together, the findings reviewed here establish mossy fiber synapses as an important component of inhibitory circuits in the hippocampus. Keywords Mossy fiber synapse . CA3 pyramidal cells . Dentate gyrus granule cells . Hippocampal interneurons . Mossy cells . Mossy fiber sprouting
Introduction The granule cells of the hippocampal dentate gyrus are perhaps the most unusual neuronal population of the brain. Granule cells are highly conserved across species (Seress and Frotscher 1990) and are born continuously throughout life, a characteristic that may be related to their role in memory formation (Schmidt-Hieber et al. 2004). Remarkably, granule cells constitutively express both excitatory and inhibitory small amino acid transmitters, viz., glutamate and γ aminobutyric acid (GABA; Sloviter et al. 1996). Although granule cells are relatively resistant to a variety of neurological insults (Nadler et al. 1978), they are exquisitely and selectively vulnerable to the absence of circulating adrenal hormones (Sloviter et al. 1989). Dentate granule cells are bipolar neurons with dendrites that extend into the molecular layer and with axons that enter the hilar region from the
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opposite pole of the cell body. In this way, a clear segregation of the input side from the output side is established, an organization that is altered in human epilepsy and animal models of the disorder (see below). The afferent input to the granule cells is clearly segregated, with fibers from the lateral and medial entorhinal cortex terminating in the outer molecular layer on distal granule cell dendrites, and commissural/associational fibers originating from hilar mossy cells forming synapses on proximal dendrites in the inner molecular layer (Blackstad 1956, 1958; Förster et al. 2006). Granule cells thus receive both cortical and hippocampal internal input in a clearly segregated manner. The thin unmyelinated axon of the granule cell (the mossy fiber) forms various types of presynaptic bouton that establish characteristic synaptic contacts with a variety of postsynaptic target cells. In the present review, we will address these different types of synapses and emphasize the synaptic connections that mossy fibers form with GABAergic inhibitory interneurons under normal and pathological conditions. Traditionally, the mossy fiber synapses with CA3 pyramidal neurons are viewed as the main granule cell output connection, forming the second synapse in the trisynaptic excitatory pathway of the hippocampal formation (Andersen et al. 1971). This view was based on early Golgi studies (Golgi 1886; Koelliker 1896; Ramón y Cajal 1911) and electron-microscopic analyses of the mossy fiber termination zone (Blackstad and Kjaerheim 1961; Hamlyn 1962). In Golgi preparations, these authors noticed that the thin mossy fiber axon gave rise to large en passant swellings and terminal expansions, which turned out to be giant mossy fiber boutons as seen by electron microscopy (EM). These presynaptic swellings resembled moss on trees and were therefore called “mossy fibers” by Ramón y Cajal (1911). Similarly large in size are the specialized postsynaptic elements, viz., the thorny excrescences, on proximal dendritic portions of CA3 pyramidal cells and large hilar neurons, with the latter being called mossy cells for the same reason (Amaral 1978). Mossy fibers stop at the border to CA1, and CA1 pyramidal cells lack thorny excrescences, as do the dendrites of GABAergic inhibitory interneurons. Thus, neither CA1 pyramidal cells nor GABAergic interneurons were thought to receive granule cell input via these highly specialized synapses (Lorente de Nó 1934). In recent years, a more complex picture of the synapses formed by granule cell axons has emerged. With the advent of new neuroanatomical techniques, the study of single identified neurons by EM and the characterization of their specific synaptic connections have become possible. Thus, the labeling of GABAergic interneurons, either by means of the Golgi/EM technique or by immunostaining, has shown that these cells are also targets of hippocampal mossy fibers (Frotscher 1985, 1989; Leranth and Frotscher 1986; Deller
and Leranth 1990; Acsády et al. 1998). Following a brief description of the “classical” mossy fiber synapses on CA3 pyramidal neurons, we will focus, in this review, on the synapses of granule cell axons with GABAergic interneurons under normal conditions and in chronic epileptic rats that show mossy fiber sprouting.
Mossy fiber synapses on CA3 pyramidal neurons Thin sectioning of a Golgi-impregnated gold-toned terminal expansion of a mossy fiber axon for EM has revealed the characteristics of this specialized synapse (Fig. 1a). The gold-labeled identified bouton is large when compared with other types of presynaptic cortical bouton. It is densely filled with clear synaptic vesicles, with a few intermingled densecore vesicles. Numerous asymmetric synaptic contacts are established with the complex spines of the postsynaptic pyramidal cell protruding deeply into the presynaptic bouton. Chicurel and Harris (1992) have found 37 such contacts in a serially reconstructed mossy fiber bouton. Asymmetric synaptic contacts are rarely observed on dendritic shafts, and these shaft synapses are likely to be mossy fiber to interneuron synaptic contacts (see below). Other contacts, mainly with dendritic shafts, are nonsynaptic puncta adhaerentia that are often observed at large synapses such as the mossy fiber synapses of the hippocampus and calyx of Held synapses in the auditory brain stem (Sätzler et al. 2002). Like their presynaptic boutons, the postsynaptic elements on CA3 pyramidal cell dendrites (the thorny excrescences) are large and often branched. Branching of spines is a rare feature of regular spines in the neocortex and hippocampus. In Fig. 1b, the postsynaptic CA3 pyramidal neuron has been Golgi-impregnated and gold-toned, allowing the identification of all spines belonging to this identified cell. Regarding their large dimensions, these complex spines have also been described as microdendrites. They often contain a spine apparatus consisting of sacs of endoplasmic reticulum associated with electron-dense plates. Occasionally, ribosomes are observed at the base of these large spines. The clear synaptic vesicles of the mossy fiber bouton are thought to contain the transmitter glutamate (Storm-Mathisen 1981; Terrian et al. 1990). Interestingly, the mossy fibers also constitutively express both glutamic acid decarboxylase 67 (GAD67) and its product, the inhibitory transmitter GABA (Sloviter et al. 1996). In addition, the mossy fiber boutons contain zinc, which allows them to be stained by the Timm sulphide silver technique for heavy metals (Timm 1958). Dense-core vesicles are often observed, and these apparently contain neuropeptides such as dynorphin, enkephalin, cholecystokinin (CCK), and neuropeptide Y (NPY) (for a review, see Henze et al. 2000). Taken together,
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Fig. 1 Identification of hippocampal mossy fiber synapses by Golgi impregnation and electron microscopy. a Of the two large mossy fiber boutons (MF1, MF2), one had been identified in the light microscope by Golgi impregnation and gold-toning. Gold grains are scattered over MF1 but still allow the large number of synaptic vesicles to be seen. The bouton establishes abundant asymmetric synaptic contacts with CA3 pyramidal cell spines (s) invaginating into the presynaptic terminal (arrows puncta adhaerentia on a proximal dendritic shaft). b Golgi impregnation of the postsynaptic pyramidal cell reveals its large, occasionally branched, complex spines (s) that are postsynaptic to mossy fiber boutons (MF). Asymmetric synaptic contacts (arrows) are present on the spines (D parent dendritic shaft). Bars 0.5 μm
the characteristic fine-structural features of mossy fiber synapses on thorny excrescences of CA3 neurons allow the unequivocal idenfication of these structures by EM and point to specialized functions of these contacts when compared with conventional small cortical synapses (Bischofberger et al. 2006).
Other targets of mossy fibers and their synaptic specializations At the light-microscopic level, the thorny excrescences, being so intimately associated with mossy fiber expansions, appeared initially to be the only target structures of granule cell axons. As mentioned above, these observations seemed
Fig. 2 Large mossy fiber boutons synapse with identified interneuron dendrites. a Golgi-impregnated and gold-toned dendritic shaft (D) of a light-microscopically identified basket cell in CA3. A large mossy fiber bouton (MF) establishes synaptic contacts both with the dendritic shaft of the identified basket cell (arrow) and with unstained spines (s) of a pyramidal neuron. b Proximal dendrite (D) of a GABAergic interneuron in the stratum lucidum of CA3, identified by postembedding immunogold labeling for GABA. A large mossy fiber terminal (MF) establishes an asymmetric synaptic contact with the GABAimmunolabeled dendrite. Bars 0.5 μm
to exclude synaptic contacts of the mossy fibers with smooth interneuron dendrites. Conventional EM of the hilar region and CA3 subsequently confirmed that the large mossy fiber boutons exclusively contacted thorny excrescences of hilar mossy cells and CA3 pyramidal neurons. To demonstrate mossy fiber synapses on interneurons, it became necessary to label these cells and study them electron-microscopically for contacts with the characteristic giant terminals of mossy fibers. By using Golgi impregnation and gold toning (Fairén et al. 1977) to label interneurons in the CA3 region, Frotscher (1985) showed that giant mossy fiber expansions established asymmetric synapses with the smooth dendrites of identified interneurons traversing the stratum lucidum. Moreover, these studies unequivocally showed that a large mossy fiber bouton could
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synapse on a smooth Golgi-impregnated interneuron dendrite and on unstained thorny excrescences of a nearby CA3 pyramidal cell (Fig. 2a). These studies with the Golgi method were later confirmed by immunostaining to identify interneuron dendrites by their transmitter phenotype (Frotscher 1989; Fig. 2b). Whereas these initial studies demonstrated that interneurons were targets of mossy fibers, they relied on the identification of large mossy fiber boutons by their unique fine-structural characteristics. This implied that smaller presynaptic elements of the mossy fibers contacting interneuron dendrites could have been neglected. Identification of smaller presynaptic elements formed by granule
cell synapses required the complete labeling of the entire mossy fiber axon with the electron-dense marker biocytin. Using this approach, Acsády et al. (1998) showed the existence of two other types of mossy fiber presynaptic bouton distinct from the giant expansions. They found that the majority of mossy fiber synapses were formed by small boutons and filopodial extensions of the giant expansions. Moreover, these two types of small mossy fiber bouton showed a clear preference for interneurons, as identified by double labeling with interneuron-specific markers. Based on these findings, Acsády and coworkers (1998) concluded that the majority of mossy fiber synapses formed synaptic connections with hippocampal interneurons, rather than
Fig. 3 Parvalbumin-positive inhibitory interneurons are targets of aberrant mossy fiber sprouting after hilar neuron loss induced by status epilepticus. a1, a2 Low- and high-magnification views of the dentate gyrus of a kainate-treated rat 22 days after status epilepticus, showing that early synaptic reorganization in the inner molecular layer (sm stratum moleculare) targets parvalbumin-positive interneurons (arrows in a1 recurrent mossy fiber terminals in the inner molecular
layer, arrows in a2 parvalbumin-positive dendrite innervated by Timm-positive terminals that leave the inner molecular layer, h hilus, sg granular layer or stratum granulosum). b–f Additional examples of parvalbumin-positive neurons in the inner molecular layer densely innervated by Timm-stained terminals of recurrent mossy fibers (arrows). Bars 25 μm (a1), 12.5 μm (a2–f). Modified from Sloviter et al. (2006)
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primarily contacting excitatory target cells (mossy cells and CA3 pyramidal cells). Some interneuron targets of mossy fibers were identified further by their morphological characteristics, examples being the various types of specialized horizontal cells in the stratum lucidum of CA3 (Gulyas et al. 1992; Soriano and Frotscher 1993a; Vida and Frotscher 2000). Together, these findings have revealed the wide of divergence of hippocampal mossy fibers that, in addition to synapsing with the complex spines of hilar mossy cells and CA3 pyramidal neurons, contact a variety of interneuron types in both the hilus and the CA3 region (Frotscher et al. 1994). The excitation of both inhibitory interneurons and excitatory target cells may provide the inhibition that filters out weak excitation and favors the transmission of strong focal excitation to intended target cells (Eccles 1973).
progresses. This observation suggests that the initial hyperexcitability is not caused by mossy fiber sprouting but rather by the initial loss of neurons (Sloviter 1987). Moreover, coincident with a fully developed band of supragranular mossy fibers, there is an increasing hyperinhibition of the granule cells, as revealed by paired-pulse suppression, and a resistance to generating epileptiform discharges in response to afferent excitation (Sloviter et al. 2006). This granule cell hyperinhibition in chronically epileptic rats is similar to the hippocampal hyperinhibition observed in human patients (Cherlow et al. 1977; Colder et al. 1996; Wilson et al. 1998). As expected, hyperinhibition in epileptic rats is abolished by application of the GABAA receptor antagonist bicuculline
Mossy fiber sprouting: increase in excitation or inhibition? Following mossy cell degeneration, which results in the denervation of their target cells in the molecular layer, granule cells “sprout” new axon collaterals and extend them into the dentate inner molecular layer (Nadler et al. 1980; Laurberg and Zimmer 1981; Frotscher and Zimmer 1983; Sloviter et al. 2006). This sprouting is a consistent feature that follows injury-induced loss of granule cell target neurons in animal models of epilepsy and in human temporal lobe epilepsy (TLE; Blümcke et al. 2000). The signals that trigger mossy fiber sprouting are still unclear, but a role for brain-derived neurotrophic factor (BDNF) has been suggested (Danzer et al. 2004; Otal et al. 2005). However, BDNF does not appear to be the only neurotrophic factor involved in this process, as mossy fiber sprouting has been found to be similar in slice cultures from wildtype mice and BDNF knockout animals (Bender et al. 1998). Since the mossy fibers give rise to excitatory synapses, the lesioninduced aberrant mossy fibers in the inner molecular layer of the dentate gyrus are generally assumed to increase granule cell excitability by forming abnormal recurrent excitatory connections among normally unconnected granule cells (Tauck and Nadler 1985). This assumption is supported by early studies on mossy fiber sprouting following denervation; by means of the Golgi/EM technique, granule cell dendrites had been identified as postsynaptic targets of sprouting mossy fibers (Frotscher and Zimmer 1983). However, more recent sequential in vivo recordings from the same chronically epileptic rats in the awake state have shown hyperexcitability of the granule cells immediately after the initial status epilepticus (SE), before mossy fiber sprouting develops, and a progressive decrease in granule cell excitability as the mossy fiber sprouting process
Fig. 4 a, b Two boutons of recurrent mossy fibers (MF) in the inner molecular layer of the dentate gyrus 10 weeks after kainate injection. The boutons establish asymmetric synaptic contacts (black arrows) on dendritic shafts (D) of GABAergic interneurons identified by postembedding immunogold labeling for GABA (white arrow thin unmyelinated preterminal mossy fiber axon, arrowheads dense-core vesicles often found in mossy fiber terminals). Bars 0.5 μm. Modified from Sloviter et al. (2006)
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(Sloviter et al. 2006). These findings, pointing to an increased GABAA-receptor-mediated inhibition after SE, suggest a possible causal relationship of the sprouting process with an increase in inhibition rather than excitation. To address this hypothesis, Sloviter and colleagues (2006) have combined Timm staining to label recurrent mossy fibers and immunostaining for the calcium-binding protein parvalbumin, which is known to be contained in major interneuron subtypes. As shown in Fig. 3, many Timm-positive recurrent mossy fibers densely innervate the dendrites of inhibitory interneurons. This result strongly suggests that mossy fibers sprouting to the inner molecular layer innervate both granule cells and interneurons, a finding that has been confirmed by GABA-immunogold labeling and EM. As seen in Fig. 4a,b, giant mossy fiber terminals establish asymmetric synaptic contacts with dendritic shafts of GABA-immunopositive neurons. Given the high degree of divergence of GABAergic interneurons in the dentate gyrus innervating thousands of granule cells, the activation of these neurons by convergent recurrent mossy fiber terminals may cause granule cell hyperinhibition and may thus form the morphological basis of the paradoxical hyperinhibition recorded in chronic epileptic rats and humans.
Conclusions The synapses made by the mossy fibers have been traditionally described as the second synapse in the hippocampal trisynaptic excitatory pathway. This excitatory chain includes synapses of fibers from the entorhinal cortex with the granule cells (first synapse), which in turn activate CA3 pyramidal neurons via mossy fiber synapses (second synapse). The third synapse is formed by contacts of the Schaffer collaterals on CA1 pyramidal cells (Andersen et al. 1971). Work over the last 30 years has established that this view of hippocampal organization as a serial trisynaptic circuit is an oversimplification. In particular, the synapses formed by mossy fibers have turned out to be more complex than anticipated. With their synapses via small boutons, filopodial extensions, and the contacts of large boutons with dendritic shafts of GABAergic neurons, mossy fiber-interneuron synapses outnumber the synapses with CA3 pyramidal cells by approximately an order of magnitude (Acsády et al. 1998). The resulting net effect on the CA3 region may be inhibition, with only a few CA3 pyramidal cells being activated in a highly selective manner (for a review of functional properties of mossy fiber synapses, see Bischofberger et al. 2006). Under pathologic conditions such as chronic epilepsy, the observed mossy fiber synapses with GABAergic interneurons may underlie the granule cell hyperinhibition recorded from chronic
epileptic animals (Sloviter et al. 2006). Activation of GABAergic dentate interneurons via sprouting mossy fibers may efficiently counteract granule cell excitation; this is likely because GABAergic basket cells, axo-axonic cells, and interneurons innervating granule cell dendrites are known for their abundant contacts with numerous granule cells (Halasy and Somogyi 1993; Soriano and Frotscher 1989, 1993b). Further complicating the story is the observation that granule cells can express GAD67 and GABA, and that the concentrations of GAD and GABA are increased seven-fold by increased activity (Sloviter et al. 1996; Sloviter 2003). Therefore, granule cells may produce inhibition indirectly, via the activation of inhibitory neurons, and directly, via the release of GABA, at least under pathophysiologic conditions (for a review, see Gutierrez 2005). The excitatory mossy fiber synapse is thus beginning to disclose its seemingly paradoxical role as an important component of hippocampal inhibitory circuits.
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