Genetic rescue of CB1 receptors on medium spiny neurons prevents loss of excitatory striatal synapses but not motor impairment in HD mice

Neurobiology of Disease

Marja D. Sepers¹  Lynn A. Raymond²  Katie Swinney³  Richard D. Palmiter³  Nephi Stella⁴  Alipi V. Naydenov⁵ 

[1] Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, WA USA;Department of Pharmacology, University of Washington, Seattle, WA USA;Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada;Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, WA USA;Medical Scientist Training Program, University of Washington, Seattle, WA USA;

关键词: Huntington's disease;    R6/2 mice;    Endocannabinoids;    CB1;    Synaptic loss;    Dendritic spines;   

DOI  :  

来源: DOAJ

【 摘 要 】

Huntington's disease (HD) is caused by an expanded polyglutamine repeat in huntingtin protein that disrupts synaptic function in specific neuronal populations and results in characteristic motor, cognitive and affective deficits. Histopathological hallmarks observed in both HD patients and genetic mouse models include the reduced expression of synaptic proteins, reduced medium spiny neuron (MSN) dendritic spine density and decreased frequency of spontaneous excitatory post-synaptic currents (sEPSCs). Early down-regulation of cannabinoid CB1 receptor expression on MSN (CB1(MSN)) is thought to participate in HD pathogenesis. Here we present a cell-specific genetic rescue of CB1(MSN) in R6/2 mice and report that treatment prevents the reduction of excitatory synaptic markers in the striatum (synaptophysin, vGLUT1 and vGLUT2), of dendritic spine density on MSNs and of MSN sEPSCs, but does not prevent motor impairment. We conclude that loss of excitatory striatal synapses in HD mice is controlled by CB1(MSN) and can be uncoupled from the motor phenotype.

【 授权许可】

Unknown