All ETDs from UAB

Advisory Committee Chair

Rita Cowell

Advisory Committee Members

Peter Detloff

Lynn Dobrunz

John Hablitz

Mathieu Lesort

David Standaert

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

GABAergic neurons are responsible for regulation of neuronal signaling through inhibition. Alterations in the delicate balance of excitation and inhibition have been observed in many neurological disorders, including neurodegenerative diseases. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, psychiatric, and cognitive disturbances. As the hallmark movement pathology of HD is hyperkinesis it is intriguing to postulate that alterations in inhibition, and by extension within GABAergic cell networks, could be part of the pathogenesis of this disorder. In order to elucidate the role of GABAergic cell populations in HD we have used behavioral paradigms, molecular techniques including immunostaining and real-time PCR, and electrophysiology to assess the consequence of mutant huntingtin (mthtt) expression on cellular functioning and viability. Using immunostaining, we observed both aggregated and soluble expression patterns throughout the brain of multiple mouse models. Investigation of transcript levels revealed alterations in cell markers and essential proteins in a variety of brain regions. Finally, electrophysiological investigations revealed pathological alterations in neuronal function concurrent with expression of mthtt. The work presented here holds implications for the understanding of the underlying disease mechanisms of HD.

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