BACKGROUND Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored. METHODS Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D1 receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum. RESULTS Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming. CONCLUSIONS These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.

中文翻译：

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纹状体直接通路 2-花生四烯酰甘油信号在社交和重复行为中的作用


背景技术内源性大麻素信号传导在调节纹状体中的突触传递中发挥重要作用，纹状体是与自闭症谱系障碍中功能障碍的中心节点有关的大脑区域。据报道，在自闭症谱系障碍小鼠模型中，内源性大麻素 2-花生四烯酰甘油 (2-AG) 介导的信号传导缺陷，但纹状体 2-AG 缺陷在与自闭症谱系障碍相关表型中的因果作用尚未被探索。方法使用条件基因敲除小鼠，通过从表达多巴胺 D1 受体或表达腺苷 A2a 受体的中型多棘神经元中删除 2-AG 的主要合成酶二酰甘油脂肪酶 α (DGLα)，研究了 2-AG 缺乏症的电生理、生化和行为影响。 (MSN) 分别确定 2-AG 信号传导在纹状体直接或间接通路中的作用。然后，我们使用病毒介导的 DGLα 缺失来研究 2-AG 缺乏对腹侧和背侧纹状体的影响。结果 从直接通路 MSN 中定向删除 DGLα 会导致社交互动缺陷、过度梳理毛发以及减少对新环境的探索。相比之下，从间接途径 MSN 中删除对所检查的任何行为测量都没有影响。直接通路 MSN 中 2-AG 的缺失也会导致谷氨酸能驱动力增加，这与逆行反馈抑制的缺失一致。背侧纹状体的亚区域 DGLα 缺失会导致社交互动的缺陷，而腹侧纹状体的缺失则会导致重复梳理毛发。结论 这些数据表明 2-AG 缺乏在社交缺陷和重复行为中发挥作用，并且证明 2-AG 在调节纹状体直接通路 MSN 中发挥关键作用。