The overall goal of this application is to enable the candidate to obtain the training needed to be able to bridge the fields of neuroscience and psychiatry and launch an independent academic research program investigating the pathophysiology of schizophrenia. The candidate plans to develop a strong foundation for the research program by learning some new basic techniques, developing skills with working with animals and expanding the candidate's knowledge of primate neurodevelopment and clinical psychiatry. Because the University of North Carolina has very strong psychiatry and neurobiology departments where colloboration is common, the university offers an ideal environment for the candidate's career development. The goals of the studies proposed in the application are to investigate the contribution of a potential mechanism, apoptosis, to the pathophysiology of schizophrenia. Although the etiology of schizophrenia is unknown, it is thought to be a late neurodevelopmental disorder and a number of neuropathoiogical findings of subtle neuronal changes in the cortex of subjects with schizophrenia suggest that synaptic circuitry is altered in this disease and that the mechanism of apoptosis may contribute to these alterations. Apoptosis is a form of cell death that consists of a cascade of regulatory checkpoints where relative levels of pro- and anti-apoptotic proteins determine whether the process will proceed to the point of neuronal breakdown and/or cell death. Previous findings of alterations in some of these checkpoints in subjects with schizophrenia compared to normal controls lend further support to implicate the mechanism of apoptosis in the pathophysiology of schizophenia. The hypothesis of the work proposed in the application is that a synaptically localized apoptotic mechanism contributes to the observed subtle neuronal degeneration observed in schizophrenia, without proceeding to the point of neuronal death. The candidate proposes to examine normal late postnatal cortical dendritic spine development and the potential involvement of the apoptotic mechanism in nonhuman primates. In order to investigate localized apoptosis in schizophrenia, the candidate proposes to examine the levels of apoptotic-associated proteins/proteases in postmortem cortical tissue samples of schizophrenic subjects and matched controls and the effect of antipsychotic medications on these proteins/proteases and on the induction of apoptosis.
| Glantz, Leisa A; Gilmore, John H; Overstreet, David H et al. (2010) Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression. Schizophr Res 118:292-9 |
| Glantz, L A; Gilmore, J H; Hamer, R M et al. (2007) Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood. Neuroscience 149:582-91 |
