Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex-dependent social interest in mice

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Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism, and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important for a better understanding of numerous pathologies and improved treatments. Several findings have suggested that an alteration of cannabinoid receptor type 1 (CB1) receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptors is still unclear, and their localisation on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptors in different neuronal populations, we used male knockout mice and their respective control littermates [total deletion (CB1−/−); specific deletion on cortical glutamatergic neurons (Glu-CB1−/−) or on GABAergic interneurons (GABA-CB1−/−), and wild-type (WT) mice treated with the CB1 antagonist/inverse agonist SR141716A (3 mg/kg). Mice were required to perform different social tasks – direct social interaction and social investigation. Direct interaction of two male mice was not modified in any group; however, when they were paired with females, Glu-CB1−/− mice showed reduced interaction. Also, exploration of the male stimulus subject in the three-chamber social investigation test was almost unaffected. The situation was completely different when a female was used as the stimulus subject. In this case, Glu-CB1−/− mice showed reduced interest in the social stimulus, mimicking the phenotype of CB1−/− or WT mice treated with SR141716A. GABA-CB1−/− mice showed the opposite phenotype, by spending more time investigating the social stimulus. In conclusion, we provide evidence that CB1 receptors specifically modulate the social investigation of female mice in a neuronal subtype-specific manner.

To better dissect the role of CB1 receptor in different neuronal subpopulations on social behavior alterations observed in several psychiatry disorders, we submitted mice with pharmacological blockage or distinct CB1 receptors deletion to two different social paradigms - animals could direct or indirectly investigate a male or ovariectomised female stimulus subject. Our results demonstrate an opposite role of CB1 receptors on glutamatergic versus GABAergic neurons in regulation of social interaction with female, but not male conspecifics.

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