This is a request for an R21 entitled """"""""Hippocampal Gene Expression in Schizophrenia"""""""" in response to the RFA MH-00-002 """"""""Gene Expression in the Nervous System"""""""". We propose to study the expression of genes in the hippocampus of normal subjects and patients with schizophrenia using a combination of gene array technology and in-situ hybridization. This research project is integrated into our ongoing study of abnormal circuitry in the hippocampus in schizophrenia. Specifically, we will test the hypothesis that an abnormality of GABAergic neurons will result in an abnormal expression of genes in subsets of hippocampal neurons. We will study two groups of schizophrenic patients, those with (T+) and without (T-) a history of treatment with neuroleptic drugs within 6 months prior to death. Both the schizophrenic and the normal control groups will be comprised of an equal number of male and female subjects. Gene array technology will be used to screen a large number of candidate genes and ESTs. Initial studies will make control vs. control comparisons to determine the amount of variation in gene expression in the normal population. This information will be used to determine the threshold at which differential expression between schizophrenics and controls can be considered significant. Brain tissue samples of several subjects will be pooled in each group to achieve a higher signal-to-noise ratio in the between-group comparisons. Genes of interest for further studies will be defined as having a) a markedly different expression in schizophrenia, b) a known function in the central nervous system and altered expression in schizophrenia, and c) differential expression in the (T-), but not (T+) schizophrenia groups. Genes of interest will then be studied with in situ hybridization in intact human brain tissue to confirm differential expression in schizophrenia and to study the subregional and cellular localization. Overall, gene profiling as outlined in this research proposal will be a powerful tool to gain information about molecular abnormalities in the hippocampus of schizophrenic subjects. The new gene array technology will be fully integrated into an existing research program to study the molecular, cellular, and systems aspects of hippocampal dysfunction in schizophrenia.
| 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 |
| Benes, F M; Matzilevich, D; Burke, R E et al. (2006) The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry 11:241-51 |
| Burke, R E; Walsh, J; Matzilevich, D et al. (2006) Mapping of hippocampal gene clusters regulated by the amygdala to nonlinkage sites for schizophrenia. Mol Psychiatry 11:158-71 |
| Benes, Francine M; Gisabella, Barbara (2006) Rat modeling for GABA defects in schizophrenia. Adv Pharmacol 54:73-93 |
| Gisabella, Barbara; Bolshakov, Vadim Y; Benes, Francine M (2005) Regulation of synaptic plasticity in a schizophrenia model. Proc Natl Acad Sci U S A 102:13301-6 |
| Benes, F M; Burke, R E; Walsh, J et al. (2004) Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus. Mol Psychiatry 9:932-45, 895 |
