부산대학교 도서관

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions. Its pathophysiological mechanisms are still poorly understood. Dominant mutations of the GNAL gene are a cause of isolated dystonia (DYT25) in patients. Some mutations result in a complete loss of function of the encoded protein, Gaolf, an adenylyl-cyclase-stimulatory G protein highly enriched in striatal projection neurons, in which it mediates the actions of dopamine and adenosine. We used male and female heterozygous Gnal knockout mice (Gnal+/-) to study how GNAL haplodeficiency is implicated in dystonia. In basal conditions, no overt dystonic movements or postures or change in locomotor activity were observed in these mice. However, Gnal haploinsufficiency altered self-grooming, motor coordination, and apparent motivation in operant conditioning, as well as spine morphology and phospho-CaMKIIß in the striatum. Following systemic administration of oxotremorine, an unselective cholinergic agonist, Gnal +/- mice developed more abnormal postures and movements than wild type mice. These effects were not caused by seizures as indicated by EEG recordings. They were prevented by M1-preferring muscarinic antagonists, telenzepine, pirenzepine, and trihexyphenidyl, which alleviates dystonic symptoms in patients. The motor defects were worsened by mecamylamine, a selective nicotinic antagonist. These oxotremorine-induced abnormalities in Gnal +/- mice were replicated by oxotremorine infusion into the striatum, but not into the cerebellum, indicating that defects in striatal neurons favor the appearance of dystonia-like movement alterations following oxotremorine. Untreated and oxotremorine-treated Gnal+/- mice provide models of presymptomic and symptomatic stages of DYT25-associated dystonia, respectively, and clues about the mechanisms underlying dystonia pathogenesis. [ABSTRACT FROM AUTHOR]