Zophrenia is a complex neuropsychiatric disorder whose etiology has remained elusive. Both neurodevelopmental and neurodegenerative hypotheses have been proposed to account for its many clinical and neuropathological features. The neurodevelopmental hypothesis can account for the observed relationship between early life neurobiological insults and a higher incidence of schizophrenia in adulthood with associated residual permanent structural and functional brain deficits. However, the neurodevelopmental perspective falls to account for a number of cardinal features including the protracted period of symptomatic dormancy between the putative insult and the emergence of clinical symptoms, the progressive clinical deterioration that affects a significant subgroup of patients, and the recent evidence for progressive pathomorphological changes in ventricular and cortical brain structures. In light of these data, we suggest that limited neurodegeneration may occur in concert with a neurodevelopmental disorder and that a dysregulation of apoptotic regulatory proteins is an ideal candidate mechanism to underlie both of these seemingly divergent processes. The hypothesis of this study is that apoptotic regulatory proteins contribute to the underlying pathophysiology of schizophrenia. The candidate has evidence that the neuroprotective Bcl-2 protein is downregulated in postmortem schizophrenic cortex. Furthermore, preliminary data suggest an association between antipsychotic treatment and higher Bcl-2 levels. Together, these findings provide a rationale for the study of apoptotic regulatory proteins in schizophrenia, both in the pathophysiology and in the treatment of this disorder. To test this hypothesis, postmortem brain tissue from schizophrenic and control groups will be assessed for Bcl-2 and caspase family proteins. These will be measured by ELISA, immunohistochemistry and Western blots. In a parallel rat model, neonatal rats will receive injections of endotoxrn (a model of infection) and MK8O1 (a model of NMDA hypofunction). Acute and long-term effects of endotoxrn and MK8O 1 will be assessed for apoptosis, Bcl-2 family proteins, and caspases as in the human post-mortem tissue. Stereological neuronal cell counting and measurement of somal size will also be assessed. Finally, young adult rats will receive typical and atypical antipsychotics to assess their effect on the apoptotic regulatory proteins.
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