Vol 4 n° 4 - Drug Development
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nimal models are important in investigating the origin and the mechanisms underlying a human disease and designing new therapies, and have been widely used in various areas of medical research.Animal models have not been, however, very popular in psychiatric research. Reproducing psychiatric disorders in animals has often been  considered  difficult, if  not  impossible. Modeling 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 reproduced in an animal. Recent new evidence about the neurobiology of this dis- ease has opened new possibilities of animal research. In particular, abnormalities in the neural circuitry involving the hippocampus, prefrontal cortex, and the dorsomedial thalamus have been reported recently, in addition to pre- viously recognized abnormal function of the dopaminer- gic system. Cytoarchitectural and molecular studies of the brain, as well as neuropsychological studies showing that schizophrenia symptoms emerge in young adulthood but subtle motor and behavioral abnormalities are present early in life, suggest a neurodevelopmental origin of the disease. To address a neurodevelopmental origin of schizophrenia, numerous studies modeling schizophrenia in animals have focused on neonatal damage of restricted brain regions in rats1-11 and in monkeys.12-15 The main objective of many of these studies is to disrupt development of the hippocam- pus, a brain area consistently implicated in human schizo- phrenia,16-25 and thus disrupt development of the wide- B a s i c   r e s e a r c h 3 6 1 Neonatal disconnection of the rat hippocampus: a neurodevelopmental model of schizophrenia Barbara K. Lipska, PhD A Keywords: animal model; schizophrenia; hippocampus; prefrontal cortex; neuro- development; neonate; locomotion; dopamine Author  affiliations:  Clinical   Brain   Disorders   Branch,   Intramural   Research Program, National Institute of Mental Health, NIH, IRP, Bethesda, Md, USA Address for correspondence: Barbara K. Lipska, 10 Center Drive, Bldg 10, Rm 4N306, Bethesda, MD 20892-1385, USA (e-mail: lipskab@intra.nimh.nih.gov) 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 mech- anisms 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 schizophrenia, including func- tional pathology in presumably critical brain regions inter- connected with the hippocampal 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 dur- ing a critical period of development, which produces sub- tle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the pre- frontal cortex (and perhaps, other interconnected late- maturing regions) and trigger behavioral changes similar to those observed in animals with the permanent excito- toxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion. Dialogues Clin Neurosci. 2002;4:361-367.