Advisory Committee Chair
Rita M Cowell
Advisory Committee Members
Roger L Albin
Douglas R Moellering
Rosalinda C Roberts
John J Hablitz
Document Type
Dissertation
Date of Award
2016
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Expression and/or function of transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is reduced in a variety of both neurodegenerative and psychiatric disorders. However, it is difficult to determine the significance of decreased PGC-1α expression and/or function in disease without knowing 1) the localization of these changes, 2) what the normal function of PGC-1α is in that specific cell-type, and 3) how its role in one neuronal population is different from its role in another. PGC-1α is highly expressed in GABAergic interneurons, and although it plays a significant role in interneuron function, several reports suggest that it also plays a role in transcriptional regulation within striatal medium spiny neurons (MSNs) as well as cortical and hippocampal pyramidal neurons (PNs). To test this hypothesis, we ablated PGC-1α in these neuronal populations using cre-lox technology and monitored the functional outcome through behavioral assays, quantitative real-time PCR, immunohistochemistry, and electrophysiology. The data presented here demonstrate that while each neuronal population is affected by PGC-1α deficiency, the precise sets of genes and the functional consequences of deficiency differ, depending on cell type and region. Reductions in PGC-1α-dependent genes lead to region-specific effects with regard to neuronal excitability in both the striato-nigral/striato-pallidal and cortico- striatal/cortico-hippocampal circuits. Changes in regional circuitry are also evident at the behavioral level, in which a deletion of PGC-1α from these neuronal populations contributes to distinct cognitive and motor effects as well as impaired responsiveness to psychostimulants. These data shed light on how cell-specific dysfunction in PGC-1α-dependent transcription contributes to distinct endophenotypes of neurological disease and suggest that precise cell-selective targeting of these pathways would need to be considered to rescue effects of PGC-1α deficiency in disease.
Recommended Citation
McMeekin, Laura, "Cell-Specific PGC-1α-Dependent Transcription: Implications for Cognitive and Motor Dysfunction" (2016). All ETDs from UAB. 2449.
https://digitalcommons.library.uab.edu/etd-collection/2449