Memory dysfunction and associated abnormalities in prefrontal-hippocampal (PFC-HIPP) circuitry are keyvulnerabilities in schizophrenia (SZ). This CIDAR application focuses on the roles of gamma aminobutyricacid (GABA), glutamate (GLU) and brain-derived neurotrophic factor (BDNF) in explaining SZ illnessprogression, domains associated with memory dysfunction and PFC-HIPP circuitry. We have demonstratedsignificant sex differences in this circuitry and in memory dysfunction, with males exhibiting worse deficitsand higher risk for severity and illness progression than females. Animal and human studies have identifiedin these brain regions, the co-localization of estrogen (ER-alpha & -beta) and androgen (AR) receptors andglucocorticoid receptors (GR) with GABA and BDNF, which in part regulate their development and ongoingphysiology. This study will test a series of hypotheses to begin to explain the increased risk for illnessprogression in SZ men versus women. We predict that sex differences in memory dysfunction and illnessprogression will be, in part, explained by GR, ER & AR-associated signaling pathways in gene expressionregulating neurotransmitters (GABA and GLU) and growth factors (such as BDNF) in HIPP and PFC. In theproposed study, we will characterize sex differences in the associations between deficits in brain activity inPFC-HIPP circuitry in response to a memory task conducted using functional magnetic resonance imaging,structural abnormalities in PFC-HIPP circuitry, and neuroendocrine dysfunction associated with these braindeficits in SZ compared with normal controls. Further, we will relate abnormalities in GABA genes, BDNF,ER, AR and GR genes to these sex differences in brain abnormalities and hormonal dysregulation and beginto validate associationsbetween GR, ER and AR mRNA, BDNF and GABA in HIPP and PFC in postmortemtissue in SZ and normal control men and women. The CIDAR consortium will allow for an adequate numberof prodromal, first episode, and chronic cases of SZ and controls (n=394) and the use of functional andstructural magnetic imaging, hormonal evaluations, molecular genetics, and postmortem tissue experimentsto test our hypotheses regarding sex differences in illness progression in SZ. An investigation of thetrajectory of sex differences at different levels of illness progression is important in that it may provideinsights into the timing of potential differential hormonal interventions for men and women with SZ.
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