All ETDs from UAB

Advisory Committee Chair

Rita M Cowell

Advisory Committee Members

Mary M Boggiano

James E Cox

David C Knight

James H Meador-Woodruff

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

The transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a master regulator of energy homeostasis in peripheral tissues, and it has been assumed that PGC-1α plays a similar role in the brain. Previous work has shown that PGC-1α localizes to neurons that express high levels of the enzyme glutamic acid decarboxylase of 67 kDa (GAD67) during early postnatal development, leading us to hypothesize that PGC-1α regulates gene expression primarily in GABAergic neurons. We initially investigated the distribution of inhibitory neuron markers in PGC-1α -/- mice and observed a striking reduction in expression of the Ca2+-binding protein parvalbumin (PV) throughout regions of the cerebrum but not the cerebellum. Other GABAergic markers, including GAD67, were unaffected in PGC-1α -/- mice, leading us to hypothesize that PGC-1α directly regulates PV without compromising neuronal viability. Accordingly, we were able to robustly induce expression of PV by overexpressing PGC-1α in neuroblastoma cells. To determine other putative targets of PGC-1α, we conducted an unbiased gene array on neuroblastoma cells overexpressing PGC-1α. Given the well-defined role of PGC-1α as a transcriptional coactivator, we hypothesized that true PGC-1α-dependent genes would be both upregulated by PGC-1α overexpression and decreased in PGC-1α -/- animals. We discovered six such genes, two of which were region-specific and four of which were globally reduced. These six genes can be broken down into three broad categories: synaptic (synaptotagmin 2, cerebrum; complexin 1, global), structural (neurofilament heavy chain, global; Pascin2, cerebellum), and metabolic (isocitrate dehydrogenase 3a, global; phytanoyl-CoA 2-hydroxylase, global). We found developmentally-upregulated genes synaptotagmin 2, complexin 1, and neurofilament heavy chain to be colocalized to neurons expressing GAD67, suggesting that PGC-1α may be required for the developmental induction of these genes in interneurons. We also found that loss of PGC-1α was accompanied by physiological abnormalities in inhibitory signaling indicative of a reduction in these genes, such as asynchronous neurotransmitter release. These studies reveal that PGC-1α is a regulator of inhibitory neuron gene expression and neurotransmission in the brain. Investigation of novel putative targets of PGC-1α in the neuropathology of disorders in which PGC-1α expression and/or function is dysregulated is warranted.

Share

COinS