developmental profile of the aberrant dopamine d2 receptor response in striatal cholinergic interneurons in dyt1 dystonia发育异常的多巴胺d2纹状体的胆碱能受体反应中间神经元dyt1肌张力障碍.pdfVIP

Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia 1,2 1,2 1 2 Giuseppe Sciamanna , Annalisa Tassone , Giuseppina Martella , Georgia Mandolesi , Francesca 1,2 1 1 1 3 2 Puglisi , Dario Cuomo , Grazia Madeo , Giulia Ponterio , David George Standaert , Paola Bonsi , Antonio Pisani1,2* 1 Department of Neuroscience, University ‘‘Tor Vergata’’, Rome, Italy, 2 Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia I.R.C.C.S., Rome, Italy, 3 Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Abstract Background: DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear. Methods and Results: We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G- proteins, as it was prevented by intrapipette GDP-b-S.