This project is focused on the cellular pathology of the schizophrenic brain. The fundamental hypothesis to be explored is that disturbances of neuronal migration and/or preprogrammed cell death in the second trimester of pregnancy will compromise the associative circuitry interconnecting prefrontal and medial temporal cortex and mediodorsal (MD) thalamus. We have observed that interstitial neurons of white matter beneath the prefrontal and temporal cortex are maldistributed in schizophrenia which is compatible with the suggestion that their normal migration to the cortex or their developmentally-regulated death cycle could have been disrupted in the second trimester of pregnancy. A disturbance in cell settling patterns in the cortex could cause a disruption of intrinsic cortical connectivity which is compatible with hypofrontality in schizophrenia and could result in secondary effects in MD and in medial temporal cortex. Neuronal pathology has been reported in both of these brain regions in schizophrenia. This pathology could result in a functional disconnection in the proposed """"""""psychosis"""""""" circuitry, a concomitant of which is down regulation of gene expression for transmitter and receptor related molecules. A unique collection of schizophrenic and control brains has been evaluated clinically, collected, matched for age, sex and autolysis time and prepared for analysis by a novel method developed in the last grant period. Anatomical, histochemical, immunohistochemical and in situ hybridization methods will be applied to the targeted brain areas to detect changes in specific cell populations, in components of the inhibitory and excitatory cortical and thalamic circuitry, and in features indicative of disordered neuronal migration or programmed cell death. Specific research aims include: quantify specific neuronal populations in the medial temporal and prefrontal cortex and MD, evaluate the relative densities of immunocytochemically defined afferent fiber systems in the cortex and MD, quantify potential changes in gene expression for transmitter and receptor related molecules, quantify and assess morphology; continue to make prospective clinical evaluations and collect brains of schizophrenic and control subjects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH054844-03
Application #
2460391
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1995-08-01
Project End
1998-06-30
Budget Start
1997-08-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Rollins, Brandi; Martin, Maureen V; Sequeira, P Adolfo et al. (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One 4:e4913
Shao, Ling; Martin, Maureen V; Watson, Stanley J et al. (2008) Mitochondrial involvement in psychiatric disorders. Ann Med 40:281-95
Vawter, M P; Tomita, H; Meng, F et al. (2006) Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11:615, 663-79
Choudary, P V; Molnar, M; Evans, S J et al. (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102:15653-8
Vawter, Marquis P; Evans, Simon; Choudary, Prabhakara et al. (2004) Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes. Neuropsychopharmacology 29:373-84
Tomita, Hiroaki; Vawter, Marquis P; Walsh, David M et al. (2004) Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain. Biol Psychiatry 55:346-52
Bunney, William E; Bunney, Blynn G; Vawter, Marquis P et al. (2003) Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders. Am J Psychiatry 160:657-66
Molnar, Margherita; Potkin, Steven G; Bunney, William E et al. (2003) MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients. Biol Psychiatry 53:39-47
Popken, G J; Bunney Jr, W E; Potkin, S G et al. (2000) Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci U S A 97:9276-80
Huntsman, M M; Tran, B V; Potkin, S G et al. (1998) Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. Proc Natl Acad Sci U S A 95:15066-71

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