developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1α发展变化在运动协调和介质带刺的神经元标记小鼠缺乏pgc-1α.pdfVIP

Developmental Alterations in Motor Coordination and Medium Spiny Neuron Markers in Mice Lacking PGC-1a 1,2 2 2 2 2 Elizabeth K. Lucas , Sarah E. Dougherty , Laura J. McMeekin , Alisa T. Trinh , Courtney S. Reid , Rita M. Cowell2* 1 Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, United States of America, 2 Department of Psychiatry Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America Abstract Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor c coactivator 1a (PGC-1a) in the pathophysiology of Huntington Disease (HD). Adult PGC-1a 2/ 2 mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1a have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1a alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1a 2/ 2 mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1a 2/ 2 mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1a 2/ 2 mice can be completely recapitulated by conditional nervous system deletion of PGC-1a, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1a 2/ 2 striatal neuron populations and