Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication.
Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication.
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DOI：
10.1038/s41467-023-42276-5
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发表时间：
2023-10-25
影响因子：
16.6
通讯作者：
Kamiya, Atsushi
中科院分区：
文献类型：
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作者：
Hasegawa, Yuto;Kim, Juhyun;Ursini, Gianluca;Jouroukhin, Yan;Zhu, Xiaolei;Miyahara, Yu;Xiong, Feiyi;Madireddy, Samskruthi;Obayashi, Mizuho;Lutz, Beat;Sawa, Akira;Brown, Solange P;Pletnikov, Mikhail V;Kamiya, Atsushi
青少年吸食大麻会增加认知障碍和精神疾病的风险。 1 型大麻素受体 (Cnr1) 不仅在神经元和星形胶质细胞中表达，还在小胶质细胞中表达，小胶质细胞在青春期形成突触连接。然而，小胶质细胞在介导大麻主要精神活性成分 δ-9-四氢大麻酚 (THC) 的不良认知影响中的作用尚不完全清楚。在这里，我们报告说，在小鼠中，青少年接触 THC 会导致内侧前额皮质 (mPFC) 中的小胶质细胞凋亡，这种情况在 16p11.2 重复模型中加剧，16p11.2 重复是精神疾病的代表性拷贝数变异 (CNV) 危险因素。这些效应由小胶质细胞 Cnr1 介导，导致 mPFC 锥体束神经元的兴奋性降低和成年后社会记忆的缺陷。我们的研究结果表明，小胶质细胞 Cnr1 可能会导致遗传易感个体暴露于大麻的不利影响。青春期接触大麻与精神疾病风险增加有关。在这里，在 16p11.2 重复的小鼠模型中，作者确定了小胶质细胞 Cnr1 在调节 THC 暴露对 mPFC 成熟和社会记忆的不利影响中的作用。
Adolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. However, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is not fully understood. Here, we report that in mice, adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in a model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings suggest the microglial Cnr1 may contribute to adverse effect of cannabis exposure in genetically vulnerable individuals. Exposure to cannabis in adolescence is associated with increased risk of psychiatric disorders. Here, in a mouse model of 16p11.2 duplication, the authors identified a role of microglial Cnr1 for mediating the adverse effect of THC exposure on mPFC maturation and social memory.