Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 226, Issue 2, Pages 465-472Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbr.2011.10.002
Keywords
Dopamine receptor; Dystonia; Long-term depression; torsinA; Trihexyphenidyl
Categories
Funding
- National Institutes of Health [NS37409, NS47466, NS47692, NS54246, NS57098, NS65273, NS72876, NS74423]
- Dystonia Medical Research Foundation
- Bachmann-Strauss Dystonia and Parkinson Foundation
- State of Illinois
- Beckman Institute for Advanced Science and Technology
- Lucille P. Markey Charitable Trust
- UAB and UF Departments of Neurology
- Tyler's Hope for a Dystonia Cure, Inc.
- Saga Medical School, Saga, Japan
- Division of Intramural Clinical and Basic Research of the National Institute on Alcohol Abuse and Alcoholism/NIH
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DYT1 early-onset generalized torsion dystonia is an inherited movement disorder associated with mutations in DYT1 that codes for torsinA protein. The most common mutation seen in this gene is a trinucleotide deletion of GAG. We previously reported a motor control deficit on a beam-walking task in our Dyt1 Delta GAG knock-in heterozygous mice. In this report we show the reversal of this motor deficit with the anticholinergic trihexyphenidyl (THP), a drug commonly used to treat movement problems in dystonia patients. THP also restored the reduced corticostriatal long-term depression (LTD) observed in these mice. Corticostriatal LTD has long been known to be dependent on D2 receptor activation. In this mouse model, striatal D2 receptors were expressed at lower quantities in comparison to wild-type mice. Furthermore, the mice were also partially resistant to FPL64176, an agonist of L-type calcium channels that have been previously reported to cause severe dystonic-like symptoms in wild-type mice. Our findings collectively suggest that altered communication between cholinergic interneurons and medium spiny neurons is responsible for the LTD deficit and that this synaptic plasticity modification may be involved in the striatal motor control abnormalities in our mouse model of DYT1 dystonia. (C) 2011 Elsevier B.V. All rights reserved.
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