Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.

Regulation of sensorimotor gating in rats by hippocampal NMDA: anatomical localization.

Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating that is reduced in humans with certain neuropsychiatric disorders, including schizophrenia, and in rats after manipulations of limbic cortico-striato-pallido-pontine circuitry. We have reported that PPI is reduced after specific manipulations of the hippocampal complex (HPC) in rats, but the mechanisms for these effects remain poorly understood. For example, dopaminergic substrates clearly regulate PPI, but the PPI-disruptive effects of intra-HPC carbachol or NMDA are not reversed by D2 receptor antagonists. This study examined the anatomical specificity within the hippocampal complex of the PPI-disruptive effects of NMDA infusion. Startle magnitude and PPI were assessed after acute bilateral infusion of NMDA (0, 0.4 or 0.8 microg) into the dorsal subiculum (DS), region CA1, the ventral subiculum (VS), the rostral entorhinal cortex (ECr) and the caudal entorhinal cortex (ECc). A dorsal-ventral gradient for NMDA effects was observed, with a dose-dependent disruption of PPI after NMDA infusion into the VS or EC, but not the DS, and with intermediate level effects observed after NMDA infusion into CA1. A second set of studies confirmed that the failure of NMDA effects in the DS did not reflect site-related differences in startle magnitude or baseline levels of PPI. These findings demonstrate the importance of the ventral, but not the dorsal HPC, in the glutamatergic regulation of PPI.

Distributed neurodegenerative changes 2-28 days after ventral hippocampal excitotoxic lesions in rats.

An enhanced sensitivity to the behavioral effects of dopamine (DA) agonists in adult rats occurs after cytotoxic lesions of the ventral hippocampus (vHPC). While some of these behavioral changes may model specific abnormalities in schizophrenia patients, little is known about the cellular events that underlie vHPC lesion-induced behavioral DA 'supersensitivity'. Neuropathological consequences of excitotoxin lesions of the vHPC were investigated in this study. Adult male rats received vehicle or ibotenic acid infusions into the vHPC, using parameters that produce an enhanced sensitivity to the prepulse inhibition-disruptive effects of the DA agonist apomorphine, 1 month post-lesion. A total of 27 rats were sacrificed, 2, 7, 14, 21 or 28 days post-lesion. Amino-cupric-silver staining demonstrated degenerative changes throughout the hippocampus, and in hippocampal efferent projections to forebrain structures, including the septal nucleus and nucleus accumbens (NAC), and within the olfactory tubercle (OT) and orbital cortex. Silver-impregnated fibers were identified in the substantia nigra reticulata (SNr), NAC, OT, septum and orbital cortex. Some degenerative changes were noted at the earliest time point (2 days post-lesion), while others were delayed in appearance. Adjacent sections stained for tyrosine hydroxylase (TH) immunocytochemistry revealed reduced TH labeling through forebrain DA terminal fields 28 days, but not 14 days after VH lesions. Excitotoxic lesions of the vHPC result in distributed neurotoxic changes in subcortical and cortical brain regions; these changes may contribute to the delayed emergence of DA-mediated behavioral abnormalities in these animals.

Ontogeny of phencyclidine and apomorphine-induced startle gating deficits in rats.

NMDA antagonists and dopamine (DA) agonists produce neuropathological and/or behavioral changes in rats that may model specific abnormalities in schizophrenia patients. In adult rats, NMDA antagonists and DA agonists disrupt sensorimotor gating-measured by prepulse inhibition (PPI)-modeling PPI deficits in schizophrenia patients. In addition, high doses of NMDA antagonists produce limbic system pathology that may model neuropathology in schizophrenia patients. We examined these behavioral and neuropathological models across development in rats. Both the NMDA antagonist phencyclidine (PCP) and the DA agonist apomorphine disrupted PPI in 16 day pups, demonstrating early developmental functionality in substrates regulating these drug effects on PPI. In contrast, PCP neurotoxicity was evident only in adult rats. Brain mechanisms responsible for the PCP disruption of PPI, and PCP-induced neurotoxicity, are dissociable across development.