The studies that will be conducted are a continuation of a two-pronged approach to investigate dopamine-innervated associative cortex in relation to schizophrenia and its treatment with neuroleptic drugs. The central goal of the studies described in the proposal is to replicate and extend our findings of a) a decreased density of interneurons, b) increased GABA-A receptor binding and c) an increased density of vertical (associative) axons, in superficial laminae, particularly layer II, of anterior cingulate cortex (ACC) of schizophrenic (SZ) patients. Taken together, these findings have suggested a model for abnormal circuitry in SZ ACC that involves excess numbers of glutamatergic associative inputs, but decreased numbers of inhibitory basket cells. The preferential localization of these findings in superficial laminae that are actively forming and differentiating at the time of birth in human brain has raised the possibility that these changes may have occurred in response to perinatal injuries that have a high prevalence in SZ patients.
SPECIFIC AIM I : Two basic strategies are being employed to study the glutamate (GLUT) and GABA systems of schizophrenic cortex. First, a high resolution technique for quantitating receptor binding activity on individual neuronal cell bodies and subregions of neuropil in individual layers is being used to investigate GABA, benzodiazepine, NMDA and PCP receptors in post-mortem ACC and other corticolimbic regions of human brains. Second, immunocytochemical approaches are being used to visualize GLUT-immunoreactive (-IR) vertical axons and GABA-IR cell bodies in superficial layers of ACC. Confounding effects of ACC post- mortem interval, fixation, hypoxia and neuroleptic exposure are controlled for by matching, regression analysis and separate evaluations of young, neuroleptic naive SZs.
SPECIFIC AIM II : Studies in rat medial prefrontal cortex (mPFC) are used to assess whether chronic neuroleptic exposure or perinatal exposure to neurotoxic doses of maternal glucocorticoids can induce changes in the intrinsic circuitry of this region. In one series of studies, adult rats are chronically exposed to either haloperidol or clozapine, while in a second series of studies, neurotoxic doses of corticosterone are administered to pregnant dams 24 hrs. prior to parturition to simulate the effects of maternal perinatal stress on pups. The various markers for the GLUT and GABA systems described above for studies of SZ cortex will be applied to rat studies. Studies using fluorescently-tagged ligands for dopamine (DA) D1 and D2 receptors and immunolocalizations of DA will also be conducted in neuroleptic-treated and steroid-treated rats. Preliminary studies are being conducted to assess the feasibility of simultaneously localizing markers for the DA system with those for GABA or GLUT in rat mPFC and, if possible, in human ACC. The long-range goal of these studies is to determine how shifts in the relationship of intrinsic and extrinsic cortical transmitters contribute to the etiology treatment of SZ.
