Microglial cannabinoid receptor type 1 mediates social memory deficits in mice produced by adolescent THC exposure and 16p11.2 duplication

Yuto Hasegawa, Juhyun Kim, Gianluca Ursini, Yan Jouroukhin, Xiaolei Zhu, Yu Miyahara, Feiyi Xiong, Samskruthi Madireddy, Mizuho Obayashi, Beat Lutz, Akira Sawa, Solange P. Brown, Mikhail V. Pletnikov () and Atsushi Kamiya ()
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Yuto Hasegawa: Johns Hopkins University School of Medicine
Juhyun Kim: Johns Hopkins University School of Medicine
Gianluca Ursini: Johns Hopkins University School of Medicine
Yan Jouroukhin: University at Buffalo
Xiaolei Zhu: Johns Hopkins University School of Medicine
Yu Miyahara: Johns Hopkins University School of Medicine
Feiyi Xiong: Johns Hopkins University School of Medicine
Samskruthi Madireddy: Johns Hopkins University School of Medicine
Mizuho Obayashi: Johns Hopkins University School of Medicine
Beat Lutz: University Medical Center of the Johannes Gutenberg University
Akira Sawa: Johns Hopkins University School of Medicine
Solange P. Brown: Johns Hopkins University School of Medicine
Mikhail V. Pletnikov: University at Buffalo
Atsushi Kamiya: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42276-5

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