All ETDs from UAB

Advisory Committee Chair

Rita Cowell

Advisory Committee Members

Stephen Watts

Tara Desilva

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

The expression of parvalbumin (Pvalb), a calcium buffering protein expressed in subsets of inhibitory neurons throughout the brain, is reduced in numerous psychiatric and neurological disorders, yet little is known about its transcriptional regulation. Previous work from the Cowell Lab has shown that the expression of Pvalb and other interneuron-specific genes in the mouse brain is dependent on the transcriptional coactivator peroxisome proliferator activated receptor coactivator 1α (PGC-1α ) and that overexpression of PGC-1α in neuroblastoma cells is sufficient to robustly induce Pvalb. The Cowell Lab determined that expression of Pvalb requires a region upstream of the human Pvalb transcription start site encompassing a consensus binding site for members of the estrogen related receptor transcription factor family. Furthermore, preliminary studies suggest that PGC-1α-mediated regulation of interneuron-specific genes may involve the transcription factor nuclear respiratory factor 1 (NRF-1). Considering that ERRα and NRF-1 have been shown to interact with PGC-1α in peripheral tissues, we sought to determine the requirement for ERRα and NRF-1 in the induction of PGC-1α-dependent genes. We found that the ERRα-selective inverse agonists XCT790 and kaempferol blocked PGC-1α-mediated upregulation of Pvalb in addition to other previously identified PGC-1α-dependent genes. However, knockdown of ERRα and NRF-1 using siRNA did not sufficiently block expression, limiting our ability to use this technique to investigate the involvement of ERRα and NRF-1 in PGC-1α-mediated gene expression. Interestingly, XCT790 and kaempferol also reduced the expression of ERRα, suggesting that these agents influenced gene expression by decreasing availability of ERRα, in addition to blocking PGC-1α/ERRα activity. Importantly, the effects of ERRα inverse agonists were specific for the newly identified interneuron-specific genes; they had no effect on gene targets of PPARγ, an established nuclear receptor known to interact with PGC-1α and additional transcription factors. Further elucidation of the mechanisms by which PGC-1α influences gene expression via ERRα (i.e. by direct or indirect modulation of ERRα and/or NRF-1 activity) will promote the development of approaches to influence Pvalb expression and interneuron function in vivo.

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