Neurotoxicity Research, 2002 Vor. 4, pp. 469-475 Y IOr&Francis ealthsciences A Neurodevelopmental Model of Schizophrenia: Neonatal Disconnection of the Hippocampus BARBARA K. LIPSKA* and DANIEL R. WEINBERGER Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, NIH, IRP, Bethesda, MD 20892, USA (Received 10 October 2001 Revised 20 May 2002 ln dqnal form 20 May 2002) In the context of our current knowledge about schizo- phrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizo- phrenia, including functional pathology in presumably critical brain regions interconnected with the hippocam- pal formation and targeted by antipsychotic drugs--the striatum/nucleus accumbens and the prefrontal cortex, and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine related behaviors. Moreover, our data show that even transient inactivation of the VH during a critical period of development, that produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected late maturing regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizo- phrenia without a gross anatomical lesion. Keywords: Animal models Schizophrenia Hippocampus Pre- frontal cortex Neurodevelopment Neonate schizophrenia is an example of a particularly difficult task, because it is a uniquely human disease, and its most prominent symptoms--hallucinations, delusions and thought disorder--cannot be repro- duced in an animal. However, recent new evidence about the neurobiology of this disease has opened new possibilities of animal research. In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizo- phrenia-like phenomena, and finally, develop poten- tial new treatments. A heuristic model, in contrast to a traditional dopamine-based model, needs to demonstrate other schizophrenia-like abnormalities besides the feature that it directly manipulates. One example is a model based on hippocampal injury, that we have been recently exploring (for review see Lipska and Weinberger, 2000). It is a heuristic model, because it triggers behavioral and molecular changes outside the hippocampus that are associ- ated with schizophrenia, enables testing the mech- anisms underlying the resulting changes, and may predict novel therapies based on newly discovered mechanisms. INTRODUCTION Animal models are important in investigating the mechanisms underlying a human disease and designing new therapies, but they have not been very popular in psychiatric research. Reproducing psychiatric disorders in animals has often been considered difficult, if not impossible. Modeling MODELING SCHIZOPHRENIA IN A N I M A L S Most conventional animal models of schizophrenia have focused on phenomena linked to dopamine, because the dopaminergic system has been strongly implicated in this disorder, as all effective anti- psychotic drugs are antagonists of dopamine *Corresponding author. Address: 10 Center Drive, Bldg. 10, Rm. 4N306, Bethesda, MD 20892-1385, USA. Tel.: + 1-301-496-9501. Fax: +1-301-402-2751. E-mail: lipskab@intra.nimh.nih.gov ISSN 1029-8428 print/lSSN 1476-3524 online 2002 Taylor & Francis Ltd DOI: 10.1080/1029842021000022089

470 B.K. LIPSKA AND D.R. WEINBERGER receptors, and dopamine agonists induce symptoms thal resemble psychosis (Kornetsky and Markowitz, 1978 McKinney and Moran, 1981 Ellenbroek and Cools, 1990 Costall and Naylor, 1995). Some of these dopamine-based models involve behavioral para- digms that were inspired by antipsychotic (i.e. antidopaminergic) pharmacology but bear no resem- blance to schizophrenia (e.g. antagonism of apomor- phine-induced emesis). Others reproduce phenomena isomorphic with selected characteristics of schizophrenia such as motor behaviors (e.g. dopamimetic drugs-induced stereotypies) and information processing deficits (e.g. apomorphine- induced prepulse inhibition of startle (PPI) abnormalities) (Costall and Naylor, 1995). These dopamine-linked behaviors, although not specific for or uniquely prominent in schizophrenia, can be at least detected and precisely quantified in non- human species and have been useful in screening drugs with a predicted mechanism of action (e.g. dopamine blockade). Thus, models based on chan- ging dopaminergic function have no construct validity, limited face validity but relatively good predictive validity. The predictive validity is to be expected given that the models are based on changing dopamine function. However, as "dopa- mine-in, dopamine-out" models (i.e. models based on direct pharmacological manipulation of the dopaminergic system and tests of behavioral out- come related to dopamine function), they precluded exploring other than dopamine-based mechanisms of the disease and discovering novel antipsychotic therapies. Drugs that were developed as a result of such models all exert antidopaminergic efficacy. Antidopaminergic drugs, however, although amelio- rative of some of the symptoms of schizophrenia, do not cure the disease. It has become increasingly clear that models based on direct manipulations of the dopamine system may have exhausted their heur- istic potential and that new strategies need to be developed to provide novel targets for the develop- ment of more effective therapeutic agents. N E O N A T A L H I P P O C A M P A L LESION M O D E L Numerous studies have focused on neonatal damage of restricted brain regions in rats (Lipska et al., 1993 Chambers et at., 1996 Flores et at., 1996 Wan et al., 1996 1998 Wan and Corbett, 1997 Black et al., 1998 Brake et al., 1999 Becker et al., 1999 Grecksch et al., 1999 Schroeder et al., 1999) and in monkeys (Beauregard and Bachevalier, 1996 Bertolino et al., 1997 Saunders et al., 1998 Bachevalier et al., 1999). The main objective of many of these studies is to disrupt development of the hippocampus, a brain area consistently implicated in human schizophrenia (Falkai and Bogerts, 1986 Murray and Lewis, 1987 Weinberger, 1987 Jeste and Lohr, 1989 Bogerts et at., 1990 Suddath et aI., 1990 Eastwood et aI., 1995 1997 Eastwood and Harrison, 1998 Weinberger 1999), and thus disrupt development of the widespread cortical and subcortical circuitry in which the hippocampus participates. The lesions were intended to involve regions of the hippocampus that directly project to the prefrontal cortex, i.e. ventral hippocampus (VH) and ventral subiculum (Jay et al., 1989 Carr and Sesack, 1996), and that correspond to the anterior hippocampus in humans, a region that shows anatomical abnormalities in schizophrenia (Suddath et al., 1990). In a series of studies, we and others have shown that neonatal excitotoxic lesions of the rat VH lead in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine related behaviors, which bear close resemblance to beha- viors seen in animals sensitized to psychostimulants. When tested as juveniles (postnatal day 35), rats with the neonatal VH lesions are less social than controls (Sams-Dodd et al., 1997), but otherwise behave normally in motor tests involving exposure to stress and dopamine agonists. In adolescence and adult- hood (postnatal day 56 and older), lesioned animals display markedly changed behaviors thought to be primarily linked to increased mesolimbic/nigro- striatal dopamine transmission (motor hyperrespon- siveness to stress and stimulants, enhanced stereotypies). They also show enhanced sensitivity to glutamate antagonists (MK-801 and PCP), deficits in PPI and latent inhibition, impaired social behaviors and working memory problems (Lipska and Weinberger, 1993 1994a,b 1995, Lipska et al., in press Becker et al., 1999 Grecksch et al., 1999 Hori et al., 1999 A1-Amin et al., 2000 A1-Amin et al., 2001), phenomena showing many parallels with schizo- phrenia, Fig. 1. Emergence of the behavioral changes in adolescence appears not to be related to the surge of gonadal hormones during puberty because a similar temporal pattern of abnormalities is observed in animals depleted of gonadal hormones prior to puberty (Lipska and Weinberger, 1994b). Notably, removal of prefrontal neurons in adult animals with the earlier hippocampal lesion restores some of the behaviors (i.e. these modulated by but not critically dependent on the prefrontal cortex, such as hyperlo- comotion after amphetamine), suggesting that aber- rant development of the prefrontal cortex in the context of early damage to the hippocampus may be a critical factor in the expression of the syndrome (Lipska et al., 1998a). In this context, it is important to emphasize that anatomical findings from postmor- tem studies and neuropsychological and neuroima- ging studies of brain function in patients with schizophrenia have implicated prefrontal cortical maldevelopment and a developmental disconnec- tion of the temporolimbic and prefrontal cortices