Gene expression studies in schizophrenia have identified a number of transcripts that have altered expression in the cerebral cortex, especially those involved in GABA-ergic and glutamatergic neurotransmission. The goal of this proposal is to place those findings firmly into the context of identified neural circuits in auditory sensory cortex. Single cell gene expression will be evaluated via custom-designed array analysis to compare the expression of multiple transcripts (>570) in distinct neuronal populations believed to be involved in the pathogenesis of schizophrenia. These experiments will identify gene expression pathways as well as specific transcripts that have altered expression, and simultaneously identify the neuron subtypes in which their expression is altered. Stereological measurements of these same neuron populations will determine whether altered gene expression is 1) accompanied by a decrease in the relative density of individual cells types, or 2) reflect gene expression alterations within intact neuronal populations. These two scenarios lead to different conclusions about the cause of altered gene expression in schizophrenia. These data will further our understanding of the etiology of schizophrenia, and provide circuitry-related models to guide pharmacotherapeutic strategies for the treatment of schizophrenia.

Public Health Relevance

Current evidence suggests that specific subsets of inhibitory neurons in the cerebral cortex may be missing, or functionally disrupted in schizophrenia. This proposal will focus on several subtypes of these neurons that are especially suspected to be involved in the pathogenesis of schizophrenia. Their gene expression profile and the relative number will be determined in postmortem samples from schizophrenia and normal brains. The findings will help identify the precise nature of schizophrenia pathology in the cerebral cortex.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BDCN-N (02))
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Meinecke, Douglas L
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Nathan Kline Institute for Psychiatric Research
United States
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Smiley, John F; Hackett, Troy A; Bleiwas, Cynthia et al. (2016) Reduced GABA neuron density in auditory cerebral cortex of subjects with major depressive disorder. J Chem Neuroanat 76:108-121
Smiley, John F; Hackett, Troy A; Preuss, Todd M et al. (2013) Hemispheric asymmetry of primary auditory cortex and Heschl's gyrus in schizophrenia and nonpsychiatric brains. Psychiatry Res 214:435-43
Smiley, John F; Bleiwas, Cynthia (2012) Embedding matrix for simultaneous processing of multiple histological samples. J Neurosci Methods 209:195-8
Ginsberg, Stephen D; Hemby, Scott E; Smiley, John F (2012) Expression profiling in neuropsychiatric disorders: emphasis on glutamate receptors in bipolar disorder. Pharmacol Biochem Behav 100:705-11
Wintle, Richard F; Lionel, Anath C; Hu, Pingzhao et al. (2011) A genotype resource for postmortem brain samples from the Autism Tissue Program. Autism Res 4:89-97
Smiley, John F; Rosoklija, Gorazd; Mancevski, Branislav et al. (2011) Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains. Psychiatry Res 192:1-11