All ETDs from UAB

Advisory Committee Chair

Yuqing Li

Advisory Committee Members

Anne Theibert

David Sweatt

David Standaert

Document Type

Thesis

Date of Award

2011

Degree Name by School

Master of Science (MS) Heersink School of Medicine

Abstract

DYT1 dystonia is an inherited movement disorder caused by a trinucleotide deletion (DeltaGAG) in the DYT1 (TOR1A) gene, which codes for the torsinA protein. Dr. Yuqing Li's laboratory previously reported the characterization of a DYT1 dystonia mouse model, a knock-in carrying DeltaGAG in Dyt1 (KI), which displays a motor learning deficit of motor skill transfer. We report here that this motor learning deficit was reversed with an anticholinergic drug, trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. We further show a potential substrate for the pathophysiology, a reduction in D2 receptors in the striatum in KI mice, which may abolish LTD induction in the striatum. KI mice are partially resistant to FPL64176, an agonist of L-type calcium channels involved in LTD induction. These data suggest that altered communication between cholinergic interneurons and medium spiny neurons may be responsible for the LTD deficit. We also show that despite not having visible twisting and repetitive movements similar to dystonia, KI mice show sustained muscle contractions as assessed by electromyographic analysis. Finally, we addressed whether the torsinADeltaE mutation is acting as a loss-of-function or a gain-of-function, or both, using electrophysiological recordings in hippocampal slices. Three mutant mouse lines were tested: heterozygous knock-out mice (+/Delta), conditional homozygous knock-out mice (cKO), and torsinADeltaE KI mice. We discovered that both +/Delta and cKO mice show enhanced LTP in the CA1 region of the hippocampus, while no change was observed in the KI mice. In contrast, KI mice showed significantly enhanced paired pulse ratios (PPRs), which were absent in +/Delta; and cKO mice. In addition, KI mice revealed a decrease in frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents in CA1 neurons, while these were not altered in +/Delta; and cKO mice. The differences in synaptic alterations between the torsinADeltaE KI and both the heterozygous and conditional homozogous knock-out of torsinA, lend support to a gain-of-function of torsinADeltaE , the mutation which underlies human dystonia.

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