Early 5‐HT6 receptor blockade prevents symptom onset in a model of adolescent cannabis abuse. Issue 5 (24th April 2020)

• Record Type: Journal Article
• Authors: Berthoux, Coralie; Hamieh, Al Mahdy; Rogliardo, Angelina; Doucet, Emilie L; Coudert, Camille; Ango, Fabrice; Grychowska, Katarzyna; Chaumont‐Dubel, Séverine; Zajdel, Pawel; Maldonado, Rafael; Bockaert, Joël; Marin, Philippe; Bécamel, Carine
• Is Part Of: EMBO molecular medicine. Volume 12:Issue 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-04-24
• Subjects: 5HT6 receptor -- adolescent cannabis abusers -- cognitive deficits -- mTOR -- synaptic transmission; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201910605
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Cannabis abuse during adolescence confers an increased risk for developing later in life cognitive deficits reminiscent of those observed in schizophrenia, suggesting common pathological mechanisms that remain poorly characterized. In line with previous findings that revealed a role of 5‐HT6 receptor‐operated mTOR activation in cognitive deficits of rodent developmental models of schizophrenia, we show that chronic administration of ∆9‐tetrahydrocannabinol (THC) to mice during adolescence induces a long‐lasting activation of mTOR in prefrontal cortex (PFC), alterations of excitatory/inhibitory balance, intrinsic properties of layer V pyramidal neurons, and long‐term depression, as well as cognitive deficits in adulthood. All are prevented by administrating a 5‐HT6 receptor antagonist or rapamycin, during adolescence. In contrast, they are still present 2 weeks after the same treatments delivered at the adult stage. Collectively, these findings suggest a role of 5‐HT6 receptor‐operated mTOR signaling in abnormalities of cortical network wiring elicited by THC at a critical period of PFC maturation and highlight the potential of 5‐HT6 receptor antagonists as early therapy to prevent cognitive symptom onset in adolescent cannabis abusers. Synopsis: Early blockade of 5‐HT6 receptor‐operated mTOR signaling could be a novel therapeutic strategy to prevent adult stage‐onset of cognitive deficits in cannabis abusers during adolescence. A long‐lasting 5‐HT6 receptor‐operated mTOR activation is induced in prefrontal cortex of adult mice following chronic administration of THC during adolescence. This non‐physiological mTOR activation causes alterations of intrinsic properties of pyramidal neurons, E/I imbalance, impairment of LTD and cognitive deficits in adulthood. All these changes are prevented by the administration of 5‐HT6 receptor antagonists or rapamycin during adolescence. Abstract : Early blockade of 5‐HT6 receptor‐operated mTOR signaling could be a novel therapeutic strategy to prevent adult stage‐onset of cognitive deficits in cannabis abusers during adolescence.