Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health.
Graduate Program in Neuroscience, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada, and.
J Neurosci. 2018 Jan 17;38(3):544-554. doi: 10.1523/JNEUROSCI.1739-17.2017. Epub 2017 Nov 30.
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 YAC128 SPNs. 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 long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD. Huntington's disease (HD) is an inherited neurodegenerative disease with no cure. Recent studies find impairment of the endocannabinoid system in animal models but the functional implication for synaptic plasticity in HD remains unclear. Sepers et al. show a selective deficit in synaptic plasticity mediated by the endocannabinoid anandamide, but not 2-arachidonoylglycerol in a mouse model of HD. The deficit is rescued by selectively elevating levels of 2-arachidonoylglycerol produced on-demand. This mechanism could be targeted in the development of future therapeutics for HD.
亨廷顿病（HD）是一种主要影响纹状体和皮质的遗传性神经退行性疾病，导致运动和认知障碍。在出现运动表型之前，HD 的动物模型显示皮质-纹状体谷氨酸信号异常。在这里，我们在 YAC128 小鼠 HD 模型中早期测试了皮质兴奋性突触到纹状体棘投射神经元（SPN）的突触可塑性。高频刺激诱导的长时程抑郁，由内源性大麻素大麻素受体 1（CB1）介导，在雄性和雌性 YAC128 SPN 中显着减弱。在 HD 中更易受影响的间接途径 SPN 受到的影响最大。我们的实验表明代谢型谷氨酸受体和内源性大麻素 2-花生四烯酸甘油依赖性可塑性，以及激动剂对直接 CB1 的激活，在 YAC128 和 FVB/N 野生型 SPN 中相似，表明突触前 CB1 正常发挥作用。这些结果与 YAC128 SPN 中内源性大麻素合成的特定后突触损伤一致。引人注目的是，尽管内源性大麻素降解的抑制作用无效，但升高 2-花生四烯酸甘油水平可恢复 YAC128 纹状体神经元的长时程抑郁。总之，这些结果对 HD 的神经保护和改善早期认知和运动缺陷具有潜在意义。亨廷顿病（HD）是一种无法治愈的遗传性神经退行性疾病。最近的研究发现，动物模型中的内源性大麻素系统受损，但 HD 中突触可塑性的功能意义尚不清楚。Sepers 等人。在 HD 小鼠模型中显示，内源性大麻素大麻素受体 1（CB1）介导的突触可塑性选择性缺陷，但 2-花生四烯酸甘油无缺陷。通过选择性提高按需产生的 2-花生四烯酸甘油水平来挽救缺陷。这种机制可能成为未来 HD 治疗药物的靶点。
