van den Buuse_CMM - Ingenta Connect

Current Molecular Medicine 2003, 3, 459-471

459

Neurodevelopmental Animal Models of Schizophrenia: Effects on Prepulse Inhibition M. Van den Buuse*1,2, B. Garner1 and M. Koch3 1 Behavioural Neuroscience Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; 2 Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia; 3 Neuropharmacology Laboratory, Institute for Brain Research, University of Bremen, Bremen, Germany

Abstract: Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

INTRODUCTION While the etiology of schizophrenia is still unknown, it is now widely considered a neurodevelopmental disorder, influenced by both genes and the environment. The neurodevelopmental hypothesis states that schizophrenia, or a predisposition to the disease, results from pre- and/or perinatal disturbances that affect normal CNS development [1-3]. Several lines of evidence indicate such a neurodevelopmental origin, including epidemiological studies, premorbid history and postmortem studies of neuropathology. Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. Among the wide range of early life factors, suggested to be associated with later development of schizophrenia, are obstetric complications, maternal infection, maternal exposure to extreme stress (e.g. death of a parent, unwanted pregnancy, wartime conditions), urban birth and severe malnutrition during early pregnancy [3-6]. A number of brain regions have been implicated in the pathophysiology of schizophrenia, most importantly the prefrontal cortex, hippocampal formation and certain subcortical structures. Unlike

*Address correspondence to this author at the Behavioural Neuroscience Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; E-mail: [email protected] 1566-5240/03 $41.00+.00

Alzheimer’s disease, the neuropathology of schizophrenia is characterized by the absence of gliosis, indicating the disorder is not degenerative in a classical sense (however, see [7, 8]). Volumetric MRI studies have detected regional brain changes in schizophrenic patients, of which the most consistent findings are enlargement of ventricles and a reduction in volume of the medial temporal and frontal lobes [9, 10]. Postmortem studies have furthermore detected cytoarchitectonic disturbances of the entorhinal region and the anterior cingulate gyrus, suggesting abnormal neuronal migration at the time of development [11, 12]. These changes are also seen in high-risk and first episode patients suggesting that structural abnormalities are present before the onset of symptoms [1, 13, 14]. In addition, premorbid studies reveal abnormalities in social and motor behaviour and an increased frequency of minor physical anomalies, slight deviations in external physical characteristics that result from a disruption of fetal development [5, 15, 16]. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of psychiatric disorders and to highlight potential new treatments, animal models are needed. Clinical and epidemiological studies do not provide clear evidence as to whether neuropathological changes © 2003 Bentham Science Publishers Ltd.

460

Current Molecular Medicine, 2003, Vol. 3, No. 5

are the cause or consequence of the disease. On the other hand, the establishment of a causal relationship between changes in brain function and behavioural perturbation can be done with animal experimentation. One of the difficulties in developing an animal model of schizophrenia is that due to the nature and complexity of the symptoms of schizophrenia it is impossible to reproduce the disease in its entirety. Nonetheless, one can attempt to mimic specific aspects or symptoms associated with the disorder [17, 18]. In the past, animal models have focused primarily on alterations of the dopamine and glutamate systems because both transmitters have been strongly implicated in the disorder [19]. Given the growing acceptance of schizophrenia being the result of disruption of normal development of the brain, there has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models ranging from neonatal lesion studies to modulation of the early postnatal environment. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, that are associated with or are similar to that seen in schizophrenia. Schizophrenia patients have fundamental deficits in attention and sensory information processing. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics [17, 18, 20]. PPI of the acoustic startle response is the normal suppression of a startle response to a strong acoustic stimulus when it is preceded by a weak sound stimulus (prepulse). The %PPI is commonly

Van den Buuse et al.

calculated as the difference between the startle amplitude with and without a prepulse, expressed as percentage of the startle amplitude without a prepulse. In rodents, PPI is commonly assessed as whole-body startle responses using a fixed prepulsepulse interval of 100 msec and prepulses of different amplitude, yielding a ‘stimulus-response curve’ (Figs. (1 & 2)). In human experiments, another common apporach is to use eye-blink responses, a fixed prepulse intensity and varying prepulse-pulse intervals. PPI reflects a mechanism that allows an individual to filter incoming sensory information such that irrelevant external stimuli are ignored and only important stimuli are attended to. Therefore, disruption of PPI may result in an overload of sensory information. PPI is a robust phenomenon that is found across species and can be studied in both humans and animals with relative technical ease. It occurs at the first exposure and therefore is not a form of conditioning and it does not show habituation or extinction [17, 18, 20]. Because of these factors, and particularly its similarity between humans and laboratory animals, PPI has become a widely used model in studies on basic neural mechanisms in schizophrenia. Startle responses are mediated by a simple brainstem circuit including the caudal pontine reticular formation [21]. Inhibition of startle responses by acoustic prepulses is mediated by parallel regions in the superior colliculus and pedunculopontine tegmental nucleus that modulate activity of the caudal pontine reticular formation. Projections from the basal ganglia and limbic system in turn modulate

Figure 1. The effect of maternal deprivation for one hour on postnatal days 1-5 and for two hours on postnatal days 6-14 on prepulse inhibition and its disruption by apomorphine (APO, 0.1 mg/kg) in male (left panel) and female (right panel) Fischer F344 rats. Female rats were at a random stage of their oestrus cycle. Apomorphine treatment significantly disrupted PPI, but there were no differences between maternally-deprived rats and controls either at baseline or after treatment.

Neurodevelopmental Animal Models of Schizophrenia


461

Figure 2. The effect of endotoxin treatment (50 µg/kg Salmonella enteridis intraperitoneally) on postnatal days 1, 3, 5 and 7 on prepulse inhibition and its disruption by apomorphine (APO, 0.1 mg/kg) in male (left panel) and female (right panel) Fischer F344 rats. Female rats were at a random stage of their oestrus cycle. Apomorphine treatment significantly disrupted PPI, but there were no differences between endotoxin-treated rats and controls either at baseline or after apomorphine injection.

activity in the pedunculopontine tegmental nucleus, an interaction that is influenced by a variety of neurotransmitters in these regions, including dopamine, GABA, glutamate and serotonin [21]. Not surprisingly, PPI can be modulated by several pharmacological manipulations, including dopamine receptor agonists, such as apomorphine, glutamate receptor antagonists, such as MK-801, and serotoninergic drugs [22]. Less is known on the effect of neurodevelopmental insults on PPI and within these studies, several different models have been used and apparently inconsistent results found (see below). The aim of this article is to review the available information on neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

POSTWEANING DEVELOPMENTAL MODELS: ISOLATION REARING Probably the most widely used neurodevelopmental model used for PPI studies has been isolation rearing. This procedure simply consists of housing rats in single cages from the time of weaning (usually at 21 days of age) until adulthood. Thus, very early development in these animals is normal, unlike in models of neonatal or prenatal interventions (see below). Several studies have shown deficits in PPI in isolation-reared rats [22]. For example, isolation-reared Sprague-Dawley rats showed significantly lower PPI at almost all prepulse intensities [23]. A similar effect was observed in Lister rats, albeit with more variability [23], and in Fischer 344 rats, but not in Lewis [24],

Fawn-Hooded or Wistar rats [25, 26]. Another study compared Sprague-Dawley, Wistar and HoodedLister rats and found an effect of isolation rearing only in Sprague-Dawleys [26]. More studies on the cause of these rat strain differences could provide valuable information on the interaction of genetic and neurotransmitter mechanisms involved in animal models of schizophrenia. The isolation-induced deficits in PPI could be reversed by pretreatment with the typical antipsychotic dopamine D2 receptor antagonists haloperidol [27] and raclopride [23], suggesting that dopaminergic hyperactivity underlies the effects of PPI. Also acute pretreatment with the atypical antipsychotic drugs seroquel, olanzapine [28], clozapine and risperidone [27] was able to reverse the PPI deficit. The effects of chronic treatment with typical and atypical antipsychotic drugs in the isolation-rearing model remain to be established. Also, the extent to which dopamine receptor blockade is involved in the action of these latter drugs, has not been studied. It should be noted, that the robustness of the PPI deficit after isolation rearing has been questioned by a number of studies. In addition to being specific for only some rat-strains (see above), isolation rearing has to be maintained until testing to induce its effect on PPI, suggesting that any behavioural and neurochemical changes induced by the isolation are not permanent. In one study, rats were weaned at three weeks of age and tested eight weeks after weaning [29]. Isolation housing for only two weeks after weaning, four weeks after weaning, or during week 3 and 4 after weaning, did not induce disruptions of PPI [29]. Only in rats that were

462


subjected to continuous isolation housing for the entire eight weeks from weaning to testing, was a deficit in PPI observed [29]. This would argue against a permanent neurodevelopmental deficit caused during a “critical developmental ‘window’” [29]. On the other hand, when rats were tested at different ages, a time-dependent effect of isolationrearing was observed [30]. Thus, after weaning at three weeks of age, if rats were tested immediately after only two weeks of isolation, no deficits were observed, whereas if they were tested immediately after either four- or six-weeks of isolation, PPI was disrupted [30]. The authors interpreted this finding as indicating that isolation during and after an age period corresponding to ‘puberty’ in the rats, was most effective in causing deficits in PPI [30]. Other authors have suggested that the deficit in PPI induced by isolation-rearing is a fragile effect because it was not found in isolation-reared rats subjected to prior testing in other behavioural paradigms, such as locomotor hyperactivity [31]. Furthermore, it could be prevented by handling the isolated rats [32], and proved sensitive to different housing conditions [33]. These difficulties indicate that caution is needed before isolation-rearing is accepted as a good model of neurodevelopmental aspects of PPI deficits in schizophrenia [22, 34]. A number of studies have suggested possible alterations in central neurochemical mechanisms that could play a role in the effect of isolation rearing on PPI. In isolation-reared rats, treatment with amphetamine caused a significantly greater increase in locomotor activity [35] and extracellular dopamine release in the nucleus accumbens than in grouphoused controls [36, 37]. This enhanced effect of amphetamine suggest mesolimbic dopaminergic hyperactivity in these animals, which could cause the PPI deficit, similar to that seen after systemic treatment of control rats with apomorphine or amphetamine [20]. Such a dopaminergic hyperactivity is furthermore consistent with the observation that treatment with haloperidol or raclopride reversed the PPI deficit (see above) [23]. While dopamine turnover was also increased in the amygdala of isolation-reared rats, dopamine turnover was decreased in the medial prefrontal cortex of these animals [38]. Surprisingly, in contrast to amphetamine-induced dopamine release, K + induced dopamine release was lower in isolationreared rats [39]. Also serotonin release in the forebrain appears to be markedly reduced in isolated rats [40]. Using microdialysis, these authors observed stimulated serotonin release in the frontal cortex after local KCl injection or novelty stress in control animals. These responses were absent in isolation-reared rats [40]. Similarly, in the nucleus accumbens, serotonin turnover was reduced [38]. These data suggest a complex range of results of isolation rearing on two major neurotransmitter systems involved in regulation of PPI. Adding to the complexity, several other neurotransmitter systems have also been implicated in the deficits in PPI


caused by isolation rearing, such as neurotensin [41], glycine/NMDA receptors [42], and synaptophysin in the hippocampus [43]. These data clearly indicate the need for further studies into this multifactorial model of neurodevelopmental disruption of PPI.

NEONATAL STRESS AND LESION MODELS A wide variety of neurodevelopmental models of schizophrenia use treatments of the neonatal rat. The background of such studies is usually the influence of early life events on the developing central nervous system and the resulting alterations in behaviour. It should be noted, that rats and mice are born at a much more immature stage of development than humans, and that neonatal interventions in these animals are perhaps better comparable with adverse events in mid-late gestation in humans. Recently, neurodevelopmental studies have used guinea pigs, which are born at a more developed stage than rats and mice [44, 45]. No matter what stage of development different animal models are aimed for, however, it is becoming clear that neonatal models are providing extensive insight into the impact of relatively short-term early adverse events on life-long behavioural development. In this respect, prenatal and neonatal neurodevelopmental models differ fundamentally from postweaning models (see above) that do not appear to induce lasting behavioural changes.

NEONATAL STRESS AND LESION MODELS: MATERNAL DEPRIVATION AND NEONATAL HANDLING It has been known for many years, particularly in the behavioural neuroendocrine literature, that temporary loss of maternal care (maternal deprivation) in a critical early period of rat development produces lasting alterations in hormone responses to stress later in life [46, 47]. For example, a 24 hour maternal deprivation at postnatal day 3 of life resulted in adulthood in rats showing a significantly greater rise in circulating corticosterone that non-deprived controls [48]. Interestingly, these animals also showed increased susceptibility to the behavioural effects of apomorphine [48] and amphetamine [49] and enhanced levels of tyrosine hydroxylase gene expression in substantia nigra, but not ventral tegmental area [48]. This apparent dopaminergic hyperactivity led Ellenbroek and coworkers to study the behaviour of such animals in a number of behavioural tests with relevance to schizophrenia, including prepulse inhibition [50]. Newborn Wistar rats were separated from their mothers for 24 hours on postnatal day 3, 6, or 9. When the offspring reached 69 days of age, PPI was significantly reduced, particularly when separation had occurred at postnatal days 6 or 9 [50, 51]. Treatment with both the typical


antipsychotic haloperidol and atypical antipsychotic quetiapine reversed the PPI deficit [50]. Interestingly, this PPI deficit was not present when the animals were tested at 34 days of age, suggesting that the effect of maternal deprivation only developed with age, particularly after ‘puberty’ in the rats [50]. Further studies by this group showed, that the maternal deprivation-induced deficit in PPI in Wistar rats was not seen in Fischer F344 rats or Lewis rats [52]. Notably, isolation rearing was effective in Fischer F344 rats, but not Lewis rats or Wistar rats (see above), suggesting important differences between the two models in terms of the influence of genetic background. Similar to the isolation-rearing model, methodological parameters influenced the magnitude of the PPI effect after maternal deprivation. For example, no effect of maternal deprivation was seen in one study where subjects were unrelated and from different dams [53]. Similarly, only a small effect was seen if maternally deprived pups were cross-fostered to a non-deprived mother [54], emphasizing the importance of the behaviour of the dam in the effect of the separation. Indeed, altered maternal behaviour has been suggested to be one the main mechanisms behind behavioural changes of pups subjected to shorter periods of maternal deprivation [46]. In these shortterm deprived animals, effects on the hypothalamicpituitary axis and behavioural parameters are often the opposite of those seen when pups were subjected to prolonged periods of stress [46]. We have measured PPI in Fischer F344 rats that were maternally-deprived for one hour on postnatal days 1-5 and for two hours on postnatal days 6-14 [55]. When tested at 9 weeks of age, male maternallydeprived rats showed increased locomotor hyperactivity responses when treated with amphetamine [55]. However, we found no significant changes in PPI in either male or female deprived rats (Fig (1)). Treatment of the rats with apomorphine induced the expected disruption of PPI, but the extent of these effects was not different between deprived rats and non-deprived controls (Fig. (1)) [55]. These findings are in line with those from other groups showing that short-term separation does not induce permanent deficits in PPI [56, 57]. Neurochemical changes have been found in the brain of rats and mice following maternal deprivation. For example, neonatal rat pups were separated from their mothers for six hours per day on ten days between days 5 and 20 of life and studied when they were eight weeks of age. Controls were separated for only five minutes on the same days [58]. Using microdialysis probes implanted into the nucleus accumbens, it was observed that basal dopamine release was not different between maternally deprived rats and controls. Infusion of K+ significantly increased perfusate levels of dopamine in both groups, however the increase was much greater in deprived rats [58]. A similar pattern was observed for the dopamine metabolites DOPAC and


463

HVA and for the serotonin metabolite 5-HIAA. Also when systemic injection of amphetamine (0.5 mg/kg) was used to stimulate dopamine release, the response was greater in maternally-deprived rats [58]. It was noted that behavioural studies had observed that similarly deprived rats showed a reduced locomotor hyperactivity response to amphetamine treatment [59], a response which is dependent on intact dopamine projections into the nucleus accumbens [60]. The reason for this apparent discrepancy is not immediately clear. Changes in postsynaptic transduction mechanisms or in other neurotransmitter systems could play a role, although only a few studies have addressed such possibilities. For example, using the same 10day separation protocol, a follow-up study investigated dopamine and serotonin turnover in ten different brain regions of male and female rats [61]. While there were increased tissue levels of dopamine in striatum of maternally-deprived rats and DOPAC/dopamine ratio was reduced in medial prefrontal cortex, serotonin levels were reduced in hippocampus and medial prefrontal cortex [61]. After a single 24-hour separation on day 9 of life, rats showed significantly reduced expression of NMDA receptor sub-units in hippocampus [62]. However, an upregulation of striatal NMDA receptors after neonatal stress has also been reported [63].

NEONATAL STRESS AND LESION MODELS: NEONATAL BRAIN LESIONS One disadvantage of prenatal, neonatal or postweaning stress models is clearly the multifactorial nature of the stress stimulus. It is therefore not surprising that investigation into the mechanisms, by which the stress stimuli induce their long-term effects, has been difficult. A more straightforward approach would then be to directly target brain areas of interest. For example, where several clinical imaging studies have suggested morphological changes in hippocampus or frontal cortex of patients with schizophrenia [4, 9, 14], a logical next step was to study the effect of lesions in hippocampal areas or frontal cortex in animal models of schizophrenia. Such studies have indeed been carried out. The drawback of such an approach is, that neurodevelopmental mechanisms in schizophrenia are unlikely to be concentrated in one single brain area. Furthermore, as discussed previously [64], lesions are always greater than the subtle neuropathological changes seen in schizophrenia brain and lesion models do not address the causes that lead to early damage in the human brain, but merely model their effects.

NEONATAL BRAIN LESIONS: HIPPOCAMPUS By far the most comprehensively studied brain area in neurodevelopmental animal studies in schizophrenia and PPI has been the hippocampus

464


[65]. Early studies by Lipska and Weinberger established that neonatal ibotenic acid injections of the ventral hippocampus induce several behavioural and neurochemical effects which would only develop after puberty. For example, these animals showed post-pubertal development of a hyperresponsiveness to the locomotor hyperactivityinducing effects of amphetamine treatment [66], reduced sensitivity to the catalepsy-inducing effects of haloperidol and increased sensitivity to the stereotypy-inducing effects of apomorphine [67]. Early gonadectomy did not prevent the occurrence of post-pubertal behavioural changes, suggesting that it was not the surge of gonadal hormones during puberty that directly or indirectly triggered the late effects [68]. Furthermore, even transient inactivation of ventral hippocampal activity with microinjection of tetrodotoxin, rather than permanent ablation with ibotenic acid, induced post-pubertal behavioural effects [69]. Taken together, these data led the authors to conclude that neonatal inactivation of the ventral hippocampus resulted in post-pubertal development of a dopaminergic hyperactivity in the mesolimbic and nigrostriatal system [64]. Such hyperactivity would predict alterations in PPI in these animals. Similar to neonatal- and post-weaning stress models, the lesion effects were dependent on the strain of rats used. Thus, unlike Sprague-Dawley rats that showed the typical post-pubertal emergence of behaviour changes, in Fischer F344 rats the lesion effects also occurred at an earlier age, albeit less severe [70]. Smaller hippocampal lesions in Fischer F344 rats produced post-pubertal effects similar to those seen in Sprague-Dawley rats. In contrast to Sprague-Dawley rats and Fischer F344 rats, there were no effects of hippocampal lesions on behaviour in Lewis rats at any age studied [70]. These strain differences are not purely the result of genetic differences as cross-fostering studies showed that maternal behaviour is also likely to be an important factor [71]. In these studies Fisher rats and Lewis rats with neonatal hippocampal lesions were crossfostered to rat mothers from the opposite strain. It was found that maternal strain, rather than pup strain, was a determining factor in the effect of the neonatal lesions. Thus, both Lewis rats and Fischer rats raised by Fischer rat mothers showed an increased amphetamine-induced locomotor hyperactivity compared to sham-operated controls, whereas neither Lewis rats nor Fischer rats raised by Lewis rat mothers showed such an effect [71]. Thus, caution appears to be needed about which rat strain to use for neonatal lesion studies. In order to elucidate which central neurotransmitter systems were involved in the effects of neontal hippocampal lesions, in one study PPI was measured in Sprague-Dawley rats at 35 and 56 days of age after ibotenic acid-induced lesion of the ventral hippocampus at 7 days of age [72]. At 56 days of age, but not 35 days, PPI was significantly disrupted. The animals showed enhanced sensitivity


to the disrupting effect of apomorphine. Thus, whereas apomorphine had no significant effect in controls, a significant disruption of the already lower PPI was induced in lesioned rats [72]. The authors suggested that mesolimbic dopaminergic hyperactivity was responsible for the observed effect on PPI. However, further work provided data that could suggest otherwise [73]. Treatment with the dopamine receptor antagonist and typical antipsychotic haloperidol [73] did not reverse the effect of neonatal lesions of the ventral hippocampus [74, 75]. On the other hand, treatment with the atypical antipsychotics clozapine, olanzapine or risperidone did reverse the PPI deficit seen after the lesions and the authors suggested that non-dopaminergic mechanisms could be involved [73]. In this respect it is noteworthy that rats with neonatal lesions of the ventral hippocampus show enhanced sensitivity to the effects of NMDAreceptor antagonists, such as MK-801 and phencyclidine [76, 77], suggesting that PPI deficits induced by the lesion are the result of altered activity in glutamatergic pathways. Interestingly, neonatal (day 7) ibotenic acid lesions of the entorhinal cortex, one of the most important sources of excitatory input into the hippocampus, did not affect PPI or its disruption by apomorphine treatment in Wistar rats (Schmadel and Koch, unpublished findings). Further neurochemical observations in rats with neonatal ventral hippocampal lesions have provided further insight into possible changes in dopaminergic and non-dopaminergic activity. In cerebrospinal fluid samples taken at 12 weeks of age, levels of the dopamine metabolites DOPAC and HVA and of the serotonin metabolite 5-HIAA did not differ between controls and rats with neonatal hippocampal lesions [78]. However, when the animals were subjected to exposure to an open field or to forced swim stress, the increase of DOPAC levels, but not HVA or 5HIAA levels, was significantly greater in lesioned rats [78]. Lesioned rats also showed hyperresponsiveness to the effect of amphetamine on locomotor activity and cerebrospinal fluid levels of DOPAC [78]. The source of the observed increased cerebrospinal fluid responses remains unclear. For example, a microdialysis study found that the increase of dopamine release after stress or amphetamine treatment was significantly reduced in neonatally lesioned rats [79]. A similar observations was made using voltammetry, a technique that uses electrochemical detection of monoamines [80], but not in another microdialysis study [81]. No differences were found in baseline release of dopamine, DOPAC, HVA, or 5-HIAA [79-81]. Similarly, no differences were found in the density of dopamine D1 or D2 receptors in striatum and nucleus accumbens [82]. In contrast, [3 H]-7-OHDPAT binding to dopamine D3 receptors was reported to be downregulated [83]. These results suggest that the increased behavioural responses seen in neonatally lesioned rats are most likely the result of changes in dopamine receptor transduction


mechanisms rather than straightforward upregulation of dopamine release. Indeed, similar to the effects of amphetamine, the hyperlocomotion induced by the direct dopamine D2/D3 receptor agonist quinpirole was greater in rats with neonatal hippocampus lesions than in controls [84]. In the absence of changes in receptor density, such an increased effect of direct postsynaptic receptor stimulation would suggest increased responsiveness of mechanisms ‘behind’ the receptor. Indeed, postsynaptic electrophysiological responses in the nucleus accumbens to stimulation of the ventral tegmental area were markedly altered in rats with neonatal hippocampal lesions [85]. Whereas in controls, cells in the accumbens responded with decreased spike firing, in lesioned rats the response was one of increased spike firing [85]. Haloperidol treatment prevented this change [85]. Control of nucleus accumbens activity by frontal cortical inputs has also been shown to be impaired [86], as were electrophysiological properties of cells in the frontal cortex [87]. In addition, the amphetamine-induced induction of c-fos expression was reduced in medial prefrontal cortex, piriform cortex, septum and dorsolateral and ventromedial striatum at 30 min after injection, although not at later time points [88]. Studies on second messenger mechanisms linked to dopamine receptors, such as adenylate cyclase, have not been conducted in rats with neonatal hippocampal lesions. Only limited data is available on effects of neonatal hippocampal lesions on neurotransmitter systems other than dopamine. Abnormalities in glutamatergic activity were suggested by observations, that lesioned rats showed hyperresponsiveness to the behavioural effects of the NMDA receptor blocker MK-801 [76, 89] and phencyclidine [77]. Similar to the effects of amphetamine, however, the increase in dopamine release in nucleus accumbens induced by phencyclidine administration was smaller in lesioned rats than in controls [77]. Although no differences were observed in [ 3 H]MK-801 binding [89], reductions of N-acetylaspartate levels were found in prefrontal cortex at 71 days of age, but not 37 days of age [90]. Aspartate release from slices of frontal cortex was significantly less in lesioned rats compared to controls [91]. Taken together, these data suggest changes in glutamatergic transmission in the brain of adult rats with neonatal hippocampal lesions in parallel to effects on the dopamine system. However, similar to dopaminergic activity, glutamate and aspartate release appear to be reduced whereas behavioural effects of glutamatergic stimulation appear to be enhanced. While most studies on the effects of neonatal hippocampal lesions were done in rats, some studies have extended these observations to primates. Thus, comparable to the age-dependent development of behavioural effects in rats, neonatal hippocampus lesions in Macaca mulatta induced reductions in social behaviour and increased


465

stereotypy in adulthood (6-8 years of age) but not at two or six months of age [92]. Early hippocampal lesions had little effect on object recognition memory, unlike amygdaloid/entorhinal cortex lesions [93]. Combined neonatal lesions encompassing hippocampus, amygdala and parts of the cortex induced a reduction of dopamine D2 receptor availability in striatum [94], an effect that could be caused by reduced receptor densities, reduced receptor affinity, or increased dopamine release. Dopamine transporter binding was not altered [94]. Injection of amphetamine into the prefrontal cortex caused a reduction of extracellular levels of dopamine in the caudate nucleus in controls and animals with adult lesions, but an increased release in animals with neonatal lesions [86]. No studies on long-term effects of early hippocampus lesions on PPI have been performed in primates.

NEONATAL BRAIN LESIONS: AMYGDALA Recently, a neurodevelopmental model involving neonatal lesions of the amygdala was introduced [74, 95]. Similar to hippocampal lesions, very early neurotoxin injections into the amygdala induced behavioural effects that only became apparent later in life. These effects included altered responses to stress [96] and reduced social interactions [97]. The animals were also more sensitive to the locomotor hyperactivity-inducing effects of phencyclidine [98] and apomorphine [99]. Autoradiography studies showed that, in lesioned rats, dopamine D2 receptor binding was reduced in olfactory tubercle, nucleus accumbens (core and shell) and substantia nigra [100]. In contrast, no differences of specific binding of a phencyclidine analogue were present in cortical areas, nucleus accumbens and caudate nucleus [100]. Dopamine concentrations were reduced in nucleus accumbens, whereas noradrenaline concentrations were reduced in medial prefrontal cortex, nucleus accumbens and caudate nucleus [100]. The authors suggested that these findings reflect increased subcortical release of dopamine, leading to reduced postsynaptic dopamine D2 receptor density and depleted presynaptic stores [100]. The altered behavioural effects of phencyclidine could be mediated indirectly by these changes in dopaminergic activity [100]. Studies on dopamine release will be needed to confirm this hypothesis. PPI was markedly reduced in rats with neonatal lesions of the amygdala, but not when the lesions were done at 21 days of age [74]. Unfortunately, the effects of dopaminergic or glutamatergic drugs or typical and atypical antipsychotics, were not determined in this model.

NEONATAL BRAIN LESIONS: FRONTAL CORTEX Neonatal lesions of the medial prefrontal cortex of rats induced hypersensitivity to the effects of

466


amphetamine on locomotor activity at 56 days of age, but not 35 days of age [101]. Similarly, these rats showed specific working memory deficits in maze tasks and impairments in fear conditioning (Schwabe, Enkel and Koch, unpublished observations). Density of dopamine D2 receptors was significantly enhanced in nucleus accumbens shell, but not other forebrain regions, after neonatal lesions of the medial prefrontal cortex [101]. In contrast, in situ hybridization studies showed that density of dopamine D1, D3 or D4 receptors was not altered [101]. These lesions furthermore caused an enhancement of nucleus accumbens dopamine release, measured by voltammetry [102]. While these behavioural and neurochemical consequences of neonatal lesions of the prefrontal cortex would predict changes in PPI, no such lesion effect was observed (Schwabe, Enkel and Koch, unpublished observations). Thus, these lesions spare PPI while causing several effects in brain areas that have been implicated in the regulation of PPI.

PRENATAL AND NEONATAL INFECTION MODELS Epidemiological studies have suggested that of the gestational factors that influence the risk of development of schizophrenia, particularly viral infection is important. For example, an elevated risk of schizophrenia was observed in both males and females exposed to infection during the 1957 influenza epidemic in Helsinki [103]. This was confirmed in other studies [104, 105]. Although no clinical studies have investigated a link between PPI deficits and prenatal infection, some experimental animal studies have attempted to model this interaction. Infection of pregnant BALB/c mice or C57BL/6 mice with human influenza virus resulted in offspring that displayed several behavioural changes, including significantly reduced PPI, particularly at higher prepulse intensities [106]. When these mice were treated with ketamine, the expected disruption of PPI was seen in controls, but an enhancement of PPI was found in mice from infected mothers [106]. When the mice were acutely treated with clozapine or chlorpromazine, the expected increase in PPI was five-fold greater in offspring from infected mothers [106]. Because the viral infection is confined mostly to the respiratory system and was not found in the brain of the developing fetus, the authors also investigated whether the viral infection per se or the immune response to it, was causing the behavioural changes in the offspring. Thus, treatment of pregnant mice with synthetic double stranded RNA poly(I:C), to simulate viral infection and evoke an immune response, caused similar changes in the offspring as after infection itself, pointing to the importance of maternal immune factors such as corticosteroids or cytokines during brain development of the fetus


[106]. In parallel studies, offspring of similarly treated mice displayed morphological changes in cortex and hippocampus and altered levels of expression of nitric oxide synthase, reelin and synaptosomeassociated protein 25 (for references, see [106]) although the importance of any of these effects for the deficits in PPI remains to be established. It is interesting to note, however, that reelin levels have been shown to be reduced in brains of patients with schizophrenia [107]. Behavioural animal studies have suggested that partial loss of reelin production can lead to reduced spine densities and loss of GABAergic neurons in the prefrontal cortex, morphological changes akin to those found in schizophrenia [108], as well as reductions of PPI [109]. Taking together the effect of maternal virus infection on reelin levels in the offspring and the important role of reelin in brain development and behaviour, it is possible that reelin acts as a ‘mediator’ of the early effects of viral infection on vulnerability to schizophrenia later in life. Also in rats, a prenatal immune challenge was found to cause PPI effects in the offspring [110]. Injection of lipopolysaccharide from Escherichia coli on alternate days during pregnancy resulted in offspring that displayed significantly reduced PPI on 60, 100, and 300 days of age. This effect was more prominent in male rats than in female rats and also more prominent with auditory prepulses than with visual prepulses [110]. The deficit in PPI at 100 days of age could be reversed by acute treatment with the typical antipsychotic haloperidol and the atypical antipsychotic clozapine [110]. In the brains of rats that had been exposed to lipopolysaccharide treatment during fetal development, histopathological and morphological changes were found in several brain areas including nucleus accumbens and amygdala. In addition, tyrosine hydroxylase immunoreactivity was increased in nucleus accumbens in these animals by more than 50% [110]. While these studies clearly show permanent effects of a prenatal immune challenge on early fetal brain development, also neonatal infection models have shown effects on PPI. New-born rats were injected with cytomegalovirus 24 hours after birth and tested from 120 days of age [111]. Baseline PPI was not altered in these animals, but the effect of apomorphine to reduce PPI was doubled in neonatally-infected animals [111]. Intracerebral injection of newborn rats with herpes simplex virus resulted in reduced PPI at the age of 37, 46 and 58 days [112]. This effect was seen when injections were done at postnatal day 2, but not day 4, and male rats were more sensitive to the effect of virus injections than female rats [112]. Also neonatal treatment with Borna disease virus caused no change in baseline PPI in Wistar rats [113], however in Fischer 344 rats this treatment did result in reduced PPI [114], emphasizing the role of genetic background in the effects of pre- and neonatal


treatments, similar to the effects see in other neurodevelopmental models (see above). In Fischer F344 rats, we investigated the effect of neonatal injection of endotoxin on postnatal day 1, 3, 5 and 7 [115] on PPI later in life (Fig. (2)). This treatment has been shown to induce reduced body weight gain and increased corticosterone responses to stress [115]. However, when the rats were tested at 10 weeks of age, this treatment did not appear to cause changes in baseline PPI or its disruption by apomorphine (Fig. (2)).

OTHER PRENATAL AND NEONATAL MODELS There have been several other experimental models where, at various stages of brain development, treatments were used to induce changes in brain development. Probably the most widely studied is prenatal treatment with the antimitotic compound methylazoxymethanol acetate (MAM) [116, 117]. Injection of MAM at gestational day 9, 10, 11, or 12 resulted in a variety of morphological and behavioural effects in offspring, depending on the day of treatment [118-122]. Some deficits in PPI were also observed, but only when treatment was conducted at gestational day 10 [123]. This selective deficit was suggested to be related to morphological effects of the treatment in the lateral entorhinal cortex, medial septum and frontal cortex [121], all of which are directly or indirectly involved in the regulation of PPI [21]. Early postnatal exposure to ethanol or to general anesthetics (mostly those enhancing GABAergic function and blocking NMDA receptors) induces apoptotic cell death in various cortical and limbic brain areas [124] and lead to behavioral impairments, mostly concerning mnemonic functions, but no changes in PPI [125]. Also other prenatal treatments have been shown to induce limited effects on PPI in rats or mice. Rats exposed to γ radiation at gestational day 15, 17, or 19 showed no significant disruption of PPI, despite showing increased startle responses [126]. In toxicological and teratological studies, prenatal toluene treatment on gestational day 7-20 [127], alcohol exposure throughout pregnancy [128], or phenytoin exposure on gestational days 7-18 [129] similarly induced no significant changes in PPI in male or female offspring. With respect to drugs of abuse, prenatal exposure to cocaine had no effect on PPI in the offspring in one study [130], but increased PPI was shown in another study [131]. In contrast, prenatal treatment with nicotine caused slight decreases in PPI in female rats, but not male rats [132]. Recently, a model of chronic placental insufficiency was developed in guinea pigs [44, 133]. This model involves unilateral ligation of the uterine artery in mid-gestation, inducing a chronic reduction


467

of supply of oxygen and nutrients to the developing foetus. When these animals are born, they are growth-restricted and display some anatomical hallmarks similar to those seen in schizophrenia [44, 133]. For example, the animals display ventricular enlargement, morphological changes in cerebral cortex and striatum, and reduced hippocampal volume [133]. Preliminary PPI experiments in these animals showed no significant changes at 4 weeks and 8 weeks of age, but reduced PPI at 12 weeks of age [134], consistent with post-pubertal development of symptoms. Similar to prenatal studies, the effect of neonatal treatment with a variety of compounds has been investigated on PPI. Neonatal treatment of rats with epidermal growth factor suppressed the expression of the catecholamine synthesizing enzyme tyrosine hydroxylase [135] and reduced PPI [135, 136]. This reduction was attenuated by clozapine treatment [135]. Neonatal metamphetamine treatment, twice daily at postnatal days 1-10, did not cause any changes in PPI, although it significantly increased startle amplitudes [137]. In contrast, treatment with phencyclidine on postnatal days 7, 9 and 11 caused marked disruption of PPI later in life, an effect that could be prevented by treatment with the antipsychotic olanzapine [8]. The phencyclidinetreated rats also showed markedly increased levels of apoptosis in the frontal cortex and up-regulation of NMDA-receptor expression, effects that could similarly be prevented by olanzapine treatment [8]. These neurochemical effects could be involved in the reduced PPI in these animals. In addition, the contrasting effect of metamphetamine and phencyclidine could indicate that early treatments aimed at glutamate, acting on NMDA-receptors, rather than dopamine acting on its receptors, could give important clues about neurodevelopmental mechanisms involved in long-term regulation of PPI. Nevertheless, early manipulations of dopaminergic activity have been shown to induce marked alterations of PPI in later life. A 93% depletion of dopamine in striatum was induced in rats after neonatal treatment with 6-hydroxydopamine [138]. In these rats, at 60 days of age, baseline PPI was unaltered [138]. However, after the mild stress of a saline injection, reduced PPI was revealed in depleted rats [138]. In addition, these rats also displayed increased sensitivity to the disruption of PPI caused by apomorphine treatment [138]. After treatment with either haloperidol or SCH23390, blocking dopamine D2 or D1 receptors respectively, no PPI deficits were observed anymore in depleted animals [139]. These results were discussed in terms of residual dopamine levels, combined with upregulated postsynaptic receptors, mediating a relatively normal PPI in the untreated condition [139]. After stress-induced dopamine release or apomorphine treatment, the increased postsynaptic densities of receptors mediate a PPI deficit that can be reversed by receptor antagonism [138, 139]. These studies also show that many of the long-term

468


effects of prenatal or neonatal treatments may not be observed in untreated control conditions because of compensatory mechanisms that developed over time. However, when the system is brought out of balance, such as after stress or agonist treatment, deficits are revealed. A recent study in our lab has shown that chronic treatment with the cannabinoid agonist WIN55-512 of pubertal, but not of adult rats reduces PPI in adults. This PPI-deficit was reversed by haloperidol treatment. Peripubertal treatment with WIN55-512 also impaired object recognition memory and instrumental responding on a progressive-ratio schedule of reinforcement (Schneider and Koch, submitted). Since puberty is a period in life during which final maturational processes of the brain occur (stabilisation or pruning of synapses, up- or downregulation of transmitter receptors etc.), we hypothesise that puberty is a vulnerable period where drugs of abuse, teratogens or other adverse environmental events can disrupt the proper development of the brain and promote neuropsychiatric disorders.

DISCUSSION AND CONCLUSIONS The studies on neurodevelopmental models and PPI so far have included a wide variety of interventions, ranging from subtle stress stimuli to toxins and surgical procedures. These studies have clearly yielded a wealth of new data and proved that early factors, of whatever nature, can profoundly influence behaviour in adulthood. However, at the same time, several of the studies do not provide clues about the neurochemical mechanism or the brain regions involved in the behavioural effects. Where involvement of brain transmitter systems was investigated, the focus was mostly on dopaminergic and glutamatergic activity. This is an important point for future studies. It may well be, that an early intervention induces marked alterations in maturational processes that could have a clear impact on behaviour, however, the long ‘time-course’ of development allows compensatory mechanisms to mask these behavioural changes. This results in a situation where baseline behaviour is apparently normal. However, when the animals are treated with a drug stimulus, exaggerated or otherwise altered responses may be obtained. For example, when only baseline PPI is tested, no differences may be found between controls and rats that have undergone a certain neonatal stress. However, when the animals are ‘challenged’ with a drug stimulus, e.g. apomorphine treatment, a much greater sensitivity to the disruptive effect of this treatment may be found. Thus, some of the studies that reported no changes in baseline PPI and interpreted this as lack of an effect of the early intervention, may need to be reevaluated and repeated to include drug challenges. Similarly, neurochemical analysis may reveal changes in the activity of neurotransmitter systems


that do not necessarily result in behavioural effects at baseline. Of particular relevance to neonatal models in general and the maternal deprivation model in particular is furthermore the nature of the stress stimulus and the role of maternal behaviour. With respect to the former, the timing of the neonatal separation appears to be important in determining the nature and severity of behavioural effects later in life [140, 141] although this has not been systematically compared in PPI studies. With respect to maternal behaviour, it has been suggested that multiple single separations of less than eight hours have little direct effect on the pups [142] and that behavioural effects that are found in these animals are more likely to be caused by changes in maternal behaviour [143]. Again, however, this has received little attention in PPI studies. Several of the studies discussed in this review revealed marked differences between rat (and mouse) strains in their sensitivity to the effects of early developmental interventions. This is usually presented merely as a methodological detail and few studies have attempted to use this finding to systematically investigate the influence of genetic factors on PPI [144, 145] in combination with neurodevelopmental interventions. A fundamental question that remains is, whether one single intervention early in development, can explain occurrence of schizophrenia symptoms much later in life. Thus, it is increasingly recognized that early developmental factors alone may not be sufficient to cause schizophrenia, but, instead, only increase relative vulnerability to the illness. This increased vulnerability will only lead to development of symptoms in combination with other, major life events later in life. This concept is now referred to in the literature as the ‘two-hit’ hypothesis of schizophrenia [146, 147]. In this model (see Fig. (3)), the ‘first hit’ consists of predisposing genetic factors and/or early environmental factors, such as those discussed above, causing anomalous neural development and subtle changes in behaviour. The ‘second hit’ consists of one or more environmental factors, such as drug abuse or social stress [146148]. The effect of these latter environmental factors (the second hit) may go unnoticed in individuals that have not been ‘primed’ by earlier genetic and/or environmental factors (the first hit) (Fig. (3)). Thus, in the ‘two-hit’ hypothesis early and late risk factors are not simply additive, but the ‘first hit’ increases vulnerability of the individual to the effects of the ‘second hit’ [146-148]. This concept can be tested by combining many of the early interventions discussed above, with additional stress factors later in life. Very few studies have in fact attempted such a combination. Repeated treatment of adult rats with phencyclidine caused increases in locomotor activity that were much more pronounced after the animals had undergone neonatal lesioning of the ventral hippocampal region as compared to sham-lesioned



469

Figure 3. The two-hit hypothesis of schizophrenia predicts that early genetic and/or environmental developmental disruptions to the developing CNS (the ‘first hit’) increase the vulnerability of the individual (also called ‘priming’ or predisposing) to subsequent, late environmental disruptions (the ‘second hit’), leading to the development of schizophrenia (bottom panel). Neither the early disruptions (middle panel) or the late disruptions (top panel) alone are able to cause the disease (adapted from [147]).

controls [149]. Treatment of adult rats with corticosterone increased expression of GABAreceptor subunits in regions of the hippocampus and this effect was more pronounced when the animals had been pretreated prenatally with corticosterone [150]. Although limited, these studies emphasize that more pronounced effects on neurodevelopment and behaviour in animal models with relevance to schizophrenia can be obtained if early interventions are combined with later treatments and/or stress. In conclusion, evidence is mounting for an important role of neurodevelopmental factors in PPI and other animal models of schizophrenia. Further studies on the mechanisms behind the effect of these factors could shed light on some of the causes of this illness in humans.

ACKNOWLEDGEMENTS The authors would like to acknowledge Dr. Deborah Hodgson, Laboratory of Neuroimmunology, School of Behavioural Sciences, University of Newcastle, Callaghan, NSW, Australia, for performing the neonatal treatments that were part of the experiments included in this paper. Dr. M. van den Buuse is supported by a Griffith Senior Research Fellowship from the University of Melbourne, Australia.

REFERENCES [1] [2]

Harrison, P. J. (1997) Curr. Opin. Neurobiol., 7, 285-289. Weinberger, D. R. (1995) In: Hirsch, S. R., Weinberger, D. R. (ed.) Schizophrenia Blackwood, London, 295-323.

[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

Waddington, J. L., Lane, A., Larkin, C. and O'Callaghan, E. (1999) Biol. Psychiat., 46, 31-39. Weinberger, D. R. (1995) Lancet, 346, 552-557. McNeil, T. F., Cantor-Graae, E. and Ismail, B. (2000) Brain Res. Brain Res. Rev., 31, 166-178. Lewis, D. A. and Levitt, P. (2002) Annu. Rev. Neurosci., 25, 409432. Ashe, P. C., Berry, M. D. and Boulton, A. A. (2001) Progr. Neuro-Psychopharmacol. Biol. Psych., 25, 691-707. Wang, C., McInnis, J., Ross-Sanchez, M., Shinnick-Gallagher, P., Wiley, J. L. and Johnson, K. M. (2001) Neuroscience, 107, 535-550. Harrison, P. J. (1999) Brain, 122, 593-624. Wright, I. C., Rabe-Hesketh, S., Woodruff, P. W., David, A. S., Murray, R. M. and Bullmore, E. T. (2000) Am. J. Psychiatry, 157, 16-25. Beckmann, H. and Senitz, D. (2002) J. Neural. Transm., 109, 421-431. Selemon, L. D. (2001) Schizophr. Bull., 27, 349-377. Lawrie, S. M., Whalley, H. C., Abukmeil, S. S., Kestelman, J. N., Donnelly, L., Miller, P., Best, J. J., Owens, D. G. and Johnstone, E. C. (2001) Biol. Psychiatry, 49, 811-823. Velakoulis, D., Wood, S. J., McGorry, P. D. and Pantelis, C. (2000) Aust. N .Z. J. Psychiatry, 34, S113-S126. McDonald, C. and Murray, R. M. (2000) Brain Res. Brain Res. Rev., 31, 130-137. Olin, S. C. and Mednick, S. A. (1996) Schizophr. Bull, 22, 223240. Geyer, M. A. and Markou, A. (1995) In: Bloom, F. E. and Kupfer, D. J. (eds.) Psychopharmacology: the fourth generation of progress Raven Press, New York, 787-798. Ellenbroek, B. A. and Cools, A. R. (1990) Behav. Pharmacol., 1, 469-490. Carlsson, A., Waters, N. and Carlsson, M. L. (1999) Biol. Psychiatry, 46, 1388-1395. Swerdlow, N. R. and Geyer, M. A. (1998) Schizophr. Bull., 24, 285-301. Koch, M. (1999) Prog. Neurobiol., 59, 107-128. Geyer, M. A., Krebs-Thomson, K., Braff, D. L. and Swerdlow, N. R. (2001) Psychopharmacology (Berl.), 156, 117-154. Geyer, M. A., Wilkinson, L. S., Humby, T. and Robbins, T. W. (1993) Biol. Psychiatry, 34, 361-372.

470 [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59]

Current Molecular Medicine, 2003, Vol. 3, No. 5 Varty, G. B. and Geyer, M. A. (1998) Behav. Neurosci., 112, 1450-1457. Hall, F. S., Huang, S. and Fong, G. (1997) Ann. NY Acad. Sci., 821, 542-544. Weiss, I. C., Di Iorio, L., Feldon, J. and Domeney, A. M. (2000) Behav. Neurosci., 114, 364-373. Varty, G. B. and Higgins, G. A. (1995) Psychopharmacology (Berl.), 122, 15-26. Bakshi, V. P., Swerdlow, N. R., Braff, D. L. and Geyer, M. A. (1998) Biol. Psychiatry, 43, 436-445. Varty, G. B., Braff, D. L. and Geyer, M. A. (1999) Behav. Brain Res., 100, 177-183. Bakshi, V. P. and Geyer, M. A. (1999) Physiol. Behav., 67, 385392. Domeney, A. M. and Feldon, J. (1998) Pharmacol. Biochem. Behav., 59, 883-890. Krebs-Thomson, K., Giracello, D., Solis, A. and Geyer, M. A. (2001) Behav. Brain Res., 120, 221-224. Weiss, I. C., Feldon, J. and Domeney, A. M. (1999) Behav. Pharmacol., 10, 139-149. Weiss, I. C. and Feldon, J. (2001) Psychopharmacology (Berl.), 156, 305-326. Zimmerberg, B. and Brett, M. B. (1992) Psychopharmacology (Berl.), 106, 474-478. Jones, G. H., Hernandez, T. D., Kendall, D. A., Marsden, C. A. and Robbins, T. W. (1992) Pharmacol. Biochem. Behav., 43, 1735. Wilkinson, L. S., Killcross, S. S., Humby, T., Hall, F. S., Geyer, M. A. and Robbins, T. W. (1994) Neuropsychopharmacology, 10, 61-72. Heidbreder, C. A., Weiss, I. C., Domeney, A. M., Pryce, C., Homberg, J., Hedou, G., Feldon, J., Moran, M. C. and Nelson, P. (2000) Neuroscience, 100, 749-768. Hall, F. S., Wilkinson, L. S., Humby, T., Inglis, W., Kendall, D. A., Marsden, C. A. and Robbins, T. W. (1998) Pharmacol. Biochem. Behav., 59, 859-872. Bickerdike, M. J., Wright, I. K. and Marsden, C. A. (1993) Behav. Pharmacol., 4, 231-236. Binder, E. B., Kinkead, B., Owens, M. J., Kilts, C. D. and Nemeroff, C. B. (2001) J. Neurosci., 21, 601-608. Bristow, L. J., Landon, L., Saywell, K. L. and Tricklebank, M. D. (1995) Psychopharmacology (Berl.), 118, 230-232. Varty, G. B., Marsden, C. A. and Higgins, G. A. (1999) Brain Research, 824, 197-203. Mallard, C., Loeliger, M., Copolov, D. and Rees, S. (2000) Neuroscience, 100, 327-333. Vaillancourt, C. and Boksa, P. (2000) Neuropsychopharmacology, 23, 654-666. Anisman, H., Zaharia, M. D., Meaney, M. J. and Merali, Z. (1998) Int. J. Dev. Neurosci., 16, 149-164. de Kloet, E. R., Rots, N. Y. and Cools, A. R. (1996) Cell Mol. Neurobiol., 16, 345-356. Rots, N. Y., de Jong, J., Workel, J. O., Levine, S., Cools, A. R. and De Kloet, E. R. (1996) J. Neuroendocrinol., 8, 501-506. Zimmerberg, B. and Shartrand, A. M. (1992) Dev. Psychobiol., 25, 213-226. Ellenbroek, B. A., van den Kroonenberg, P. T. and Cools, A. R. (1998) Schizophr. Res., 30, 251-260. Husum, H., Termeer, E., Mathe, A. A., Bolwig, T. G. and Ellenbroek, B. A. (2002) Neuropharmacology, 42, 798-806. Ellenbroek, B. A. and Cools, A. R. (2000) Neuropsychopharmacology, 23, 99-106. Lehmann, J., Pryce, C. R. and Feldon, J. (2000) Schizophr. Res., 41, 365-371. Ellenbroek, B. A. and Cools, A. R. (2002) Pharmacol. Biochem. Behav., 73, 177-184. Garner, B., Hodgson, D. and Van den Buuse, M. (2002) Proc. Austr. Neurosci. Soc., 13, 228. Finamore, T. L. and Port, R. L. (2000) Physiol. Behav., 69, 527530. Pryce, C. R., Bettschen, D., Bahr, N. I. and Feldon, J. (2001) Behav. Neurosci., 115, 71-83. Hall, F. S., Wilkinson, L. S., Humby, T. and Robbins, T. W. (1999) Synapse, 32, 37-43. Matthews, K., Hall, F. S., Wilkinson, L. S. and Robbins, T. W. (1996) Psychopharmacology, 126, 75-84.

Van den Buuse et al. [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95]

Kelly, P. H., Seviour, P. W. and Iversen, S. D. (1975) Brain Res., 94, 507-522. Matthews, K., Dalley, J. W., Matthews, C., Tsai, T. H. and Robbins, T. W. (2001) Synapse, 40, 1-10. Roceri, M., Hendriks, W., Racagni, G., Ellenbroek, B. A. and Riva, M. A. (2002) Mol. Psychiatry, 7, 609-616. Sircar, R., Mallinson, K., Goldbloom, L. M. and Kehoe, P. (2001) Brain Res., 904, 145-148. Lillrank, S. M., Lipska, B. K. and Weinberger, D. R. (1995) Clin. Neurosci., 3, 98-104. Lipska, B. K. and Weinberger, D. R. (2000) Neuropsychopharmacology, 23, 223-239. Lipska, B. K., Jaskiw, G. E. and Weinberger, D. R. (1993) Neuropsychopharmacology, 9, 67-75. Lipska, B. K. and Weinberger, D. R. (1993) Dev. Brain Res., 75, 213-222. Lipska, B. K. and Weinberger, D. R. (1994) Dev. Brain Res., 78, 253-258. Lipska, B. K., Halim, N. D., Segal, P. N. and Weinberger, D. R. (2002) J. Neurosci., 22, 2835-2842. Lipska, B. K. and Weinberger, D. R. (1995) Proc. Nat. Acad. Sci. USA, 92, 8906-8910. Wood, G. K., Marcotte, E. R., Quirion, R. and Srivastava, L. K. (2001) Eur J. Neurosci., 14, 1030-1034. Lipska, B. K., Swerdlow, N. R., Geyer, M. A., Jaskiw, G. E., Braff, D. L. and Weinberger, D. R. (1995) Psychopharmacology (Berl.), 122, 35-43. Le Pen, G. and Moreau, J. L. (2002) Neuropsychopharmacology, 27, 1-11. Daenen, E. W. P. M., Wolterink, G., Van der Heyden, J. A., Kruse, C. G. and van Ree, J. M. (2003) E u r Neuropsychopharmacol, (in press). Le Pen, G., Grottick, A. J., Higgins, G. A., Martin, J. R., Jenck, F. and Moreau, J. L. (2000) Behav. Pharmacol., 11, 257-268. Al-Amin, H. A., Weinberger, D. R. and Lipska, B. K. (2000) Behav. Pharmacol., 11, 269-278. Kato, K., Shishido, T., Ono, M., Shishido, K., Kobayashi, M., Suzuki, H., Nabeshima, T., Furukawa, H. and Niwa, S. (2000) Psychopharmacology, 150, 163-169. Wan, R. Q., Hartman, H. and Corbett, R. (1998) Physiol. Behav., 65, 429-436. Lillrank, S. M., Lipska, B. K., Kolachana, B. S. and Weinberger, D. R. (1999) J. Neural. Transm., 106, 183-196. Brake, W. G., Sullivan, R. M., Flores, G., Srivastava, L. K. and Gratton, A. (1999) Brain Res., 831, 25-32. Wan, R. Q., Giovanni, A., Kafka, S. H. and Corbett, R. (1996) Behav. Brain Res., 78, 211-223. Lillrank, S. M., Lipska, B. K., Weinberger, D. R., Fredholm, B. B., Fuxe, K. and Ferre, S. (1999) Neurochem. Int., 34, 235-244. Flores, G., Barbeau, D., Quirion, R. and Srivastava, L. K. (1996) J. Neurosci., 16, 2020-2026. Wan, R. Q. and Corbett, R. (1997) Neuropsychopharmacology, 16, 259-268. Goto, Y. and O'Donnell, P. (2002) J. Neurosci., 22, 9070-9077. Saunders, R. C., Kolachana, B. S., Bachevalier, J. and Weinberger, D. R. (1998) Nature, 393, 169-171. O'Donnell, P., Lewis, B. L., Weinberger, D. R. and Lipska, B. K. (2002) Cereb. Cortex, 12, 975-982. Lillrank, S. M., Lipska, B. K., Bachus, S. E., Wood, G. K. and Weinberger, D. R. (1996) Synapse, 23, 292-301. Al-Amin, H. A., Shannon Weickert, C., Weinberger, D. R. and Lipska, B. K. (2001) Biol. Psychiatry, 49, 528-539. Bertolino, A., Roffman, J. L., Lipska, B. K., van Gelderen, P., Olson, A. and Weinberger, D. R. (2002) Cereb. Cortex, 12, 983990. Schroeder, H., Grecksch, G., Becker, A., Bogerts, B. and Hoellt, V. (1999) Psychopharmacology (Berl.), 145, 61-66. Beauregard, M., Malkova, L. and Bachevalier, J. (1995) Neuroreport, 6, 2521-2526. Bachevalier, J., Beauregard, M. and Alvarado, M. C. (1999) Behav. Neurosci., 113, 1127-1151. Heinz, A., Saunders, R. C., Kolachana, B. S., Jones, D. W., Gorey, J. G., Bachevalier, J. and Weinberger, D. R. (1999) Synapse, 32, 71-79. Wolterink, G., Daenen, L. E., Dubbeldam, S., Gerrits, M. A., van Rijn, R., Kruse, C. G., Van Der Heijden, J. A. and Van Ree, J. M. (2001) Eur. Neuropsychopharmacol., 11, 51-59.

Neurodevelopmental Animal Models of Schizophrenia [96] [97] [98]

[99]

[100] [101] [102] [103] [104] [105] [106] [107]

[108] [109] [110] [111] [112] [113] [114] [115] [116] [117]

[118] [119] [120] [121]

Daenen, E. W., Van der Heyden, J. A., Kruse, C. G., Wolterink, G. and Van Ree, J. M. (2001) Brain Res., 918, 153-165. Daenen, E. W., Wolterink, G., Gerrits, M. A. and Van Ree, J. M. (2002) Behav. Brain Res., 136, 571-582. Daenen, E. W. P. M., Wolterink, G. and van Ree, J. M. (1999) Neonatal lesions of the rat brain; a model of neurodevelopmental psychopathological disorders Ph.D. thesis, Utrecht, The Netherlands, 127-142. Daenen, E. W. P. M., Wolterink, G. and van Ree, J. M. (1999) Neonatal lesions of the rat brain; a model of neurodevelopmental psychopathological disorders Ph.D. thesis, Utrecht, The Netherlands, 143-157. Bouwmeester, H. 2002 Neurodevelopmental aspects of neonatal amygdala lesions in the rat - neuroanatomical and neurochemical studies. Ph.D. thesis. Flores, G., Wood, G. K., Liang, J. J., Quirion, R. and Srivastava, L. K. (1996) J. Neurosci., 16, 7366-7375. Brake, W. G., Flores, G., Francis, D., Meaney, M. J., Srivastava, L. K. and Gratton, A. (2000) Neuroscience, 96, 687695. Mednick, S. A., Machon, R. A., Huttunen, M. O. and Bonett, D. (1988) Arch. Gen. Psychiatry, 45, 189-192. Rantakallio, P., Jones, P., Moring, J. and Von Wendt, L. (1997) Int. J. Epidemiol., 26, 837-843. Sham, P. C., O'Callaghan, E., Takei, N., Murray, G. K., Hare, E. H. and Murray, R. M. (1992) Br. J. Psychiatry, 160, 461-466. Shi, L., Fatemi, S. H., Sidwell, R. W. and Patterson, P. H. (2003) J. Neurosci., 23, 297-302. Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., Uzunov, D. P., Smalheiser, N. R., Davis, J. M., Pandey, G. N., Pappas, G. D., Tueting, P., Sharma, R. P. and Costa, E. (1998) Proc. Natl. Acad. Sci. USA, 95, 15718-15723. Liu, W. S., Pesold, C., Rodriguez, M. A., Carboni, G., Auta, J., Lacor, P., Larson, J., Condie, B. G., Guidotti, A. and Costa, E. (2001) Proc. Natl. Acad. Sci. USA, 98, 3477-3482. Pappas, G. D., Kriho, V. and Pesold, C. (2001) J. Neurocytol., 30, 413-425. Borrell, J., Vela, J. M., Arevalo-Martin, A., Molina-Holgado, E. and Guaza, C. (2002) Neuropsychopharmacology, 26, 204-215. Rothschild, D. M., O'Grady, M. and Wecker, L. (1999) J. Neurosci. Res., 57, 429-434. Engel, J. A., Zhang, J., Bergstrom, T., Conradi, N., Forkstam, C., Liljeroth, A. and Svensson, L. (2000) Brain Res., 863, 233240. Pletnikov, M. V., Rubin, S. A., Carbone, K. M., Moran, T. H. and Schwartz, G. J. (2001) Brain Res. Dev. Brain Res., 126, 1-12. Pletnikov, M. V., Rubin, S. A., Vogel, M. W., Moran, T. H. and Carbone, K. M. (2002) Brain Res., 944, 97-107. Hodgson, D. M., Knott, B. and Walker, F. R. (2001) Pediatr. Res., 50, 750-755. Cattabeni, F. and Di Luca, M. (1997) Physiol. Rev., 77, 199-215. Colacitti, C., Sancini, G., DeBiasi, S., Franceschetti, S., Caputi, A., Frassoni, C., Cattabeni, F., Avanzini, G., Spreafico, R., Di Luca, M. and Battaglia, G. (1999) J. Neuropathol. Exp. Neurol., 58, 92-106. Fiore, M., Korf, J., Angelucci, F., Talamini, L. and Aloe, L. (2000) Physiol. Behav., 71, 57-67. Fiore, M., Talamini, L., Angelucci, F., Koch, T., Aloe, L. and Korf, J. (1999) Neuropharmacology, 38, 857-869. Talamini, L. M., Koch, T., Luiten, P. G., Koolhaas, J. M. and Korf, J. (1999) Brain Res., 847, 105-120. Talamini, L. M., Koch, T., Ter Horst, G. J. and Korf, J. (1998) Brain Res., 789, 293-306.

Current Molecular Medicine, 2003, Vol. 3, No. 5 [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150]

471

Moore, H., West, A. R. and Grace, A. A. (1999) Biol. Psychiatry, 46, 40-55. Talamini, L. M., Ellenbroek, B., Koch, T. and Korf, J. (2000) Ann. NY Acad. Sci., 911, 486-494. Ikonomidou, C., Bittigau, P., Koch, C., Genz, K., Hoerster, F., Felderhoff-Mueser, U., Tenkova, T., Dikranian, K. and Olney, J. W. (2001) Biochem. Pharmacol., 62, 401-405. Jevtovic-Todorovic, V., Hartman, R. E., Izumi, Y., Benshoff, N. D., Dikranian, K., Zorumski, C. F., Olney, J. W. and Wozniak, D. F. (2003) J. Neurosci., 23, 876-882. Mintz, M., Yovel, G., Gigi, A. and Myslobodsky, M. S. (1998) Brain Res. Bull, 45, 289-296. Hougaard, K. S., Hass, U., Lund, S. P. and Simonsen, L. (1999) Neurotoxicol. Teratol., 21, 241-250. Potter, B. M. and Berntson, G. G. (1987) Neurotoxicol. Teratol., 9, 17-21. Vorhees, C. V. and Minck, D. R. (1989) Neurotoxicol. Teratol., 11, 295-305. Foss, J. A. and Riley, E. P. (1991) Neurotoxicol. Teratol., 13, 541-546. Overstreet, D. H., Moy, S. S., Lubin, D. A., Gause, L. R., Lieberman, J. A. and Johns, J. M. (2000) Physiol. Behav., 70, 149-156. Popke, E. J., Tizabi, Y., Rahman, M. A., Nespor, S. M. and Grunberg, N. E. (1997) Pharmacol. Biochem. Behav., 58, 843849. Mallard, E. A., Rehn, A., Rees, S., Tolcos, M. and Copolov, D. (1999) Schizophrenia Res., 40, 11-21. Rehn, A., Van den Buuse, M., Copolov, D. and Rees, S. (2003) Proc. Austr. Neurosci. Soc., 14, Oral-01-04. Futamura, T., Kakita, A., Tohmi, M., Sotoyama, H., Takahashi, H. and Nawa, H. (2003) Mol. Psychiatry, 8, 19-29. Henck, J. W., Reindel, J. F. and Anderson, J. A. (2001) Toxicol. Sci., 62, 80-91. Vorhees, C. V., Reed, T. M., Schilling, M. S., Acuff-Smith, K. D., Fisher, J. E. and Moran, M. S. (1996) Neurotoxicol. Teratol., 18, 135-139. Schwarzkopf, S. B., Mitra, T. and Bruno, J. P. (1992) Biol. Psychiatry, 31, 759-773. Schwarzkopf, S. B., Bruno, J. P., Mitra, T. and Ison, J. R. (1996) Psychopharmacology (Berl.), 123, 258-266. Lehmann, J. and Feldon, J. (2000) Rev. Neurosci., 11, 383-408. van Oers, H. J. J., de Kloet, E. R. and Levine, S. (1998) Dev. Brain Res., 111, 245-252. Levine, S., Huchton, D. M., Wiener, S. G. and Rosenfeld, P. (1991) Dev. Psychobiol., 24, 547-558. Francis, D. D. and Meaney, M. J. (1999) Curr. Opin. Neurobiol., 9, 128-134. Joober, R., Zarate, J. M., Rouleau, G. A., Skamene, E. and Boksa, P. (2002) Neuropsychopharmacology, 27, 765-781. Palmer, A. A., Breen, L. L., Flodman, P., Conti, L. H., Spence, M. A. and Printz, M. P. (2003) Psychopharmacology (Berl.), 165, 270-279. Bayer, T. A., Falkai, P. and Maier, W. (1999) J. Psychiatr. Res., 33, 543-548. Maynard, T. M., Sikich, L., Lieberman, J. A. and LaMantia, A. S. (2001) Schizophrenia Bull., 27, 457-476. Murray, R. M. and Fearon, P. (1999) J. Psychiatr. Res., 33, 497499. Hori, T., Subramaniam, S., Srivastava, L. K. and Quirion, R. (2000) Neuropharmacology, 39, 2478-2491. Stone, D. J., Walsh, J. P., Sebro, R., Stevens, R., Pantazopolous, H. and Benes, F. M. (2001) Hippocampus, 11, 492-507.