All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Matthew Goldberg

Michelle Gray

Gwendalyn King

Vladimir Parpura

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. Multiple studies have indicated the importance of mutant huntingtin (mHTT) in astrocytes to HD pathogenesis. Increased extracellular glutamate levels were observed after evoking SNARE-dependent exocytosis from cultured mHTT expressing astrocytes. To determine whether astrocytic SNARE-dependent exocytosis contributed to behavioral and neuropathological changes in vivo, we crossed BACHD mice to dominant negative SNARE (dnSNARE) mice and analyzed behavioral and neuropathological phenotypes. First, we found that reduc-ing astrocytic SNARE-dependent exocytosis had differential effects on the psychiatric-like and motor phenotypes observed in BACHD mice where motor coordination was normalized while psychiatric like behaviors were worse. Furthermore, astrocytic SNARE-dependent exocytosis contributed to abnormal motor and psychiatric-like behaviors in normal wildtype mice. Neuropathologically, a reduction in astrocytic SNARE-dependent exocytosis protected against striatal atrophy. Furthermore, an increase in GABA transporter 3 expression observed in BACHD mice was normalized to wildtype level after reducing astrocytic SNARE-dependent exocytosis. Modulation of SNARE- iv dependent exocytosis in astrocytes revealed the importance of this mechanism to behavioral and neuropathological phenotypes in these HD mice as well as normal mice. Lastly, analyses of striatal extracellular amino acid levels in vivo in awake BACHD mice by microdialysis and HPLC-ED revealed an increase in extracellular GABA levels and no change in glutamate or glutamine levels in aged BACHD mice. Taken together, this work suggests that astrocytic SNARE-dependent exocytosis has a complex role in motor and psychiatric-like behaviors and that extracellular amino acid levels in vivo may be influenced by cell-cell interactions.

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