390. Neonatal damage of the rat hippocampus results in a constellation of schizophrenia- like phenomena

Abstract

To model schizophrenia in a rat, we have disrupted development of the hippocampus, a brain area consistently implicated in human schizophrenia, by infusing excitotoxin (ibotenic acid, 3 μg in 0.3 μl) into the ventral hippocampus of neonatal (postnatal days 3 or 7) rats. Neonatal excitotoxic lesions produce a temporally specific pattern of abnormalities in a number of dopamine-related behavioral paradigms, disrupt sensorimotor gating and latent inhibition, impair social behaviors and cause working memory problems. Antipsychotic drugs normalize some of the abnormal behaviors. The postpubertal emergence of behavioral changes in males appears not to be related to the surge of gonadal hormones during puberty. Several pieces of evidence suggest that the function of the prefrontal cortex is altered as a result of this lesion. Removal of prefrontal neurons in animals with earlier neonatal hippocampal lesion restores some of the behaviors. Rats with neonatal but not adult lesions of the hippocampus are impaired in the delayed alternation task, a paradigm sensitive to prefrontal cortical disruptions, and show molecular changes in the prefrontal cortex (ΔfosB expression is increased, GAD67 tends to be reduced). Moreover, in in vivo proton magnetic resonance spectroscopy studies, neonatally lesioned rats show attenuated prefrontal cortical levels of N-acetylaspartate (NAA), a measure of neuronal integrity. Recent electrophysiological studies also suggest subtle changes in the function of prefrontal cortical neurons in response to the stimulation of the ventral segmental area (firing pattern of pyramidal neurons is altered upon stimulation). The results of our studies raise the possibility that aberrant development of the prefrontal cortex may be a critical factor in the onset of the neonatal hippocampal lesion syndrome.