The Postmortem Gene Expression Core of this CIDAR application will serve to facilitate the understanding of how genes that are postulated in the proposed projects to play a role in schizophrenia (SZ) disease progression may contribute to the disturbances of neural circuitry in layer 3 of the dorsolateral prefrontal and auditory association cortices (Brodmann's areas 9 and 42, respectively) and in the CA2/3 region of the hippocampus. The overarching hypothesis that guides the proposed studies is that the onset and progression of SZ is the manifestation of a process of progressive loss of synaptic connectivities. Specifically, disturbances of the modulation of pyramidal neurons by GABAergic local circuit neurons, especially the fast-spiking cells that contain the calcium-binding protein pan/albumin (PV), and vice versa, are central to the pathophysiology of synaptic deficits. Consequently, oscillatory synchrony both within and between brain regions will be compromised, which, together with myelination deficits, contributes to the functional deterioration that is characteristic of the early course of SZ. Thus, we will use laser capture microdissection combined with quantitative real-time polymerasechain reaction to quantify the mRNA for neuregulin (NRG)1, brain-derived neurotrophic factor (BDNF), androgen receptor, and GABA receptor alpha 1 and alpha 2 subunits in pyramidal cells, and NRG1 receptor tyrosine kinase ErbB4, BDNF receptor tyrosine kinase TrkB, alpha and beta isoforms of the estrogen receptor, NMDA NR2A subunit, and kainate receptor GluRS subunit in PV-immunoreactive neurons in a cohort of 20 SZ and 20 normal control subjects that are matched for age, postmortem interval, sex, and pH. We will also explore the feasibility of measuring gene expression in individual oligodendrocytes (OL) by quantifying 4 OL-associated genes that have been found in white matter microarray studies to be downregulated in SZ: myelin associated glycoprotein, myelin/ oligodendrocyte glycoprotein, NRG1 receptor tyrosine kinase ErbBS, and 2'3'-cyclic nucleotide 3'- phosphodiesterase. Human brain specimens have been obtained from the Harvard Brain Tissue Resource Center, of which Dr. Woo is the Associate Director. Findings of the proposed studies hold the promise of offering conceptually entirely novel insight into how SZ disease progression can be attenuated or perhaps even arrested by correcting the disturbances of the underlying neural circuits.
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