Role of Transcription factors in the action of Antipsychotic Drugs Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Conventional, typical antipsychotics such as haloperidol are useful in treating the symptoms but do not improve cognitive impairment and exhibit undesirable side effects. Alternately, atypical antipsychotics, olanzapine and ziprasidone have been shown to have superior efficacy on cognitive impairments, fewer extrapyramidal side effects and a broader range of therapeutic effects. The precise molecular mechanisms governing the effects of antipsychotics are not well understood. We hypothesize that the antipsychotic action is via neuroplasticity and synaptic remodeling due to changes in gene expression. Earlier work from multiple research groups have shown robust alterations in gene expression of the Fos, Egr, retinoid acid nuclear receptor and Nurr family of transcription factors (TFs) in response to APD administration. Typical and atypical APDs also exhibit differences in brain sub-region induction patterns of these TFs. Although the induction of TFs by APDs has been investigated for over a decade, very little is known about the functional activity of these TFs and the downstream gene targets that they modulate. The fact that different classes of APDs differentially modulate TF expression based on brain region and duration of drug administration indicates that TFs could play an important role in the mechanism of APD action.
The aim of this R21 Exploratory grant is to characterize transcription factor functional activation by employing a combination of chromatin immunoprecipitation (ChIP) and promoter arrays. TF functional activity will be characterized in the prefrontal cortex and striatum, two well characterized brain regions implicated in schizophrenia as well as APD action. The neuronal phenotype of TF-induced cells will be determined by a combination of immunohistochemical and in situ hybridization analysis. This study will enhance our understanding of the role played by transcription factors in mediating APD action and gene expression. The results from these studies should lead to an RO1 proposal aimed at extending these findings by manipulating specific TFs and investigating their influence in behavioral and genetic models.

Public Health Relevance

The molecular mechanism of antipsychotic drug action is not well understood. Several studies have reported the brain region specific induction of DNA-binding proteins (transcription factors, TF) by these drugs. The functional activity of these transcription factors using microarray chips.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MNG-B (01))
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Beckel-Mitchener, Andrea C
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Yale University
Schools of Medicine
New Haven
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Duman, Catharine H; Newton, Samuel S (2013) Evaluating effects of EPO in rodent behavioral assays related to depression. Methods Mol Biol 982:127-40
Girgenti, Matthew James; Nisenbaum, Laura K; Bymaster, Franklin et al. (2010) Antipsychotic-induced gene regulation in multiple brain regions. J Neurochem 113:175-87