Pathomechanisms of Dopamine Dysregulation in DYT1 Dystonia: Targets for Therapeutics
Technical Report,15 Sep 2015,14 Sep 2016
Emory University Atlanta United States
Pagination or Media Count:
The causes of dystonia are not understood but abnormal signaling by the neurotransmitter dopamine occurs in many inherited forms of dystonia, including DYT1 dystonia. Abnormalities in dopamine signaling that are observed in patients with DYT1 are also observed in DYT1 knockin mice, suggesting a reduction in dopamine release. Further, our preliminary data suggest that trihexyphenidyl THP, the most commonly used medication for the treatment of dystonia, corrects the dopaminergic defect. The overarching hypothesis is the defect in DA transmission is caused by abnormal vesicular function or abnormal receptor-mediated regulation of release and rescued by THP. The specific aims are 1 To characterize presynaptic defects that mediate abnormal DA release in DYT1delta E knockin mice by assessing VMAT2 function, vesicle utilization, the ultrastructure of DA terminals, and D2 DA autoreceptor function nicotinic AChR nAChR heteroreceptors function. 2 To determine the mechanisms underlying the dopaminergic response to THP using FSCV and microdialysis to to identify the role of nAChRs in the regulation of DA release by THP and to identify the specific mAChRs that mediate DA release.
- Medicine and Medical Research