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

卷:71

Article

Naydenov, Alipi V.^1,2  Sepers, Marja D.³  Swinney, Katie⁴  Raymond, Lynn A.³  Palmiter, Richard D.⁵  Stella, Nephi⁴ 

[1] Univ Washington, Med Scientist Training Program, Seattle, WA 98195 USA

[2] Univ Washington, Grad Program Neurobiol & Behav, Seattle, WA 98195 USA

[3] Univ British Columbia, Brain Res Ctr, Dept Psychiat, Vancouver, BC V5Z 1M9, Canada

[4] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA

[5] Univ Washington, Howard Hughes Med Inst, Dept Biochem, Seattle, WA 98195 USA

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

DOI  :  10.1016/j.nbd.2014.08.009

来源: Elsevier

【 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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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