This proposal describes a series of studies that have emanated from previous investigations in this laboratory suggesting that three replicatible structural differences may exist in schizophrenic cortex. These findings include a) a reduced density of small interneurons, b) an increased number of vertical, associative axons, and c) a decreased size of neuronal aggregates in layer II. the proposed studies will seek to replicate these findings further to evaluate their generalizability and specificity for schizophrenia. In addition, we are proposing to extend these investigations to the entorhinal cortex and hippocampus, two other corticolimbic brain regions implicate in the etiology of this disorder. The first two findings indicated above have lead to the hypothesis that alterations in GABAergic inhibitory and glutamatergic excitatory elements in intrinsic cortical elements may occur in schizophrenic brain. Accordingly, we intend to perform autoradiographic localization of the GABA-A and NMDA-sensitive glutamate receptors to determine whether up- and/or down-regulation, respectively, of these two binding sites may occur in schizophrenics. The benzodiazepine and PCP receptors, which have been implicated in the mediation of symptoms associated with schizophrenia and are also believed to form a complex with the GABA and NMDA binding sites, respectively, will also be studied. The autoradiography will be performed using tritium-labelled ligands and emulsion-dipped coverslips to optimize spatial resolution. This approach will permit quantitative determinations of the numbers of autoradiographic grains found in neuropil versus either small interneurons or large pyramidal cells in individual layers and sub- regions. Dilapidation will be used to control for the effect of differential quenching on the development of grains. The effects of confounding variables such as age, post-mortem interval, fixation, hypoxia and neuroleptic exposure will be evaluated using multivariate statistical approaches. Attempts will be made to determine whether changes in small neurons counts and vertical axon numbers, correlate with alterations in GABA-A or NMDA receptor binding. Overall, the design of these studies is aimed at determining whether the differences occurring among schizophrenic patients may have appeared before, during or after the onset of the illness and be either of etiologic or epiphenomenal significance to this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH042261-04
Application #
3381436
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1987-09-01
Project End
1995-07-31
Budget Start
1990-09-01
Budget End
1991-07-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
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Subburaju, Sivan; Benes, Francine M (2012) Induction of the GABA cell phenotype: an in vitro model for studying neurodevelopmental disorders. PLoS One 7:e33352
Sheng, Guoqing; Demers, Matthew; Subburaju, Sivan et al. (2012) Differences in the circuitry-based association of copy numbers and gene expression between the hippocampi of patients with schizophrenia and the hippocampi of patients with bipolar disorder. Arch Gen Psychiatry 69:550-61
Benes, Francine M (2012) Nicotinic receptors and functional regulation of GABA cell microcircuitry in bipolar disorder and schizophrenia. Handb Exp Pharmacol :401-17
Gisabella, Barbara; Bolshakov, Vadim Y; Benes, Francine M (2012) Kainate receptor-mediated modulation of hippocampal fast spiking interneurons in a rat model of schizophrenia. PLoS One 7:e32483
Benes, Francine M; Lim, Benjamin; Subburaju, Sivan (2009) Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars. Proc Natl Acad Sci U S A 106:11731-6
Lisman, John E; Coyle, Joseph T; Green, Robert W et al. (2008) Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 31:234-42
Woo, Tsung-Ung W; Shrestha, Kevin; Lamb, Dorian et al. (2008) N-methyl-D-aspartate receptor and calbindin-containing neurons in the anterior cingulate cortex in schizophrenia and bipolar disorder. Biol Psychiatry 64:803-9
Buttner, Ned; Bhattacharyya, Sujoy; Walsh, John et al. (2007) DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia. Schizophr Res 93:33-41
Benes, Francine M; Lim, Benjamin; Matzilevich, David et al. (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci U S A 104:10164-9

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