期刊
JOURNAL OF NEUROSCIENCE
卷 38, 期 3, 页码 544-554出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1739-17.2017
关键词
endocannabinoid; Huntington disease; striatum
资金
- Cure Huntington's Disease Initiative Foundation
- Canadian Institutes of Health Research [FDN-143210]
- U.S. National Institutes of Health [DA011322, DA021696]
Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128SPNs. Indirect pathway SPNs, which are more vulnerable in HD, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol-dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored longterm depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD.
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