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; Atsushi Kamiya

doi:10.1038/s41467-023-42276-5

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

Nat Commun. 2023 Oct 25;14(1):6559. doi: 10.1038/s41467-023-42276-5.

Authors

Yuto Hasegawa¹, Juhyun Kim^{1

2}, Gianluca Ursini^{1

3}, Yan Jouroukhin⁴, Xiaolei Zhu¹, Yu Miyahara¹, Feiyi Xiong¹, Samskruthi Madireddy¹, Mizuho Obayashi¹, Beat Lutz^{5

6}, Akira Sawa^{1

7

8

9

10

11}, Solange P Brown^{7

12}, Mikhail V Pletnikov¹³, Atsushi Kamiya¹⁴

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Korea Brain Research Institute, Daegu, Republic of Korea.
³ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
⁴ Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences SUNY, University at Buffalo, Buffalo, NY, USA.
⁵ Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁶ Leibniz Institute for Resilience Research (LIR) gGmbH, Mainz, Germany.
⁷ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
¹² Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA.
¹³ Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences SUNY, University at Buffalo, Buffalo, NY, USA. mvpletni@buffalo.edu.
¹⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. akamiya1@jhmi.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cannabinoid Receptor Agonists
DNA Copy Number Variations
Dronabinol* / adverse effects
Memory Disorders / chemically induced
Memory Disorders / genetics
Mice
Microglia*
Receptors, Cannabinoid / genetics

Substances

Cannabinoid Receptor Agonists
Dronabinol
Receptors, Cannabinoid

Abstract

Publication types

MeSH terms

Substances

Grants and funding