Journal
EMBO MOLECULAR MEDICINE
Volume 12, Issue 5, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201910605
Keywords
5HT(6) receptor; adolescent cannabis abusers; cognitive deficits; mTOR; synaptic transmission
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Funding
- CNRS
- INSERM
- University of Montpellier
- Labex EpiGenMed
- Fondation pour la Recherche Medicale (FRM, Physiopathologie de l'Addiction program) [DPA20140629800]
- Fondation FondaMental
- ANR [17-CE16-0013-01]
- Gouvernement de la Nouvelle Caledonie
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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 increment 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.
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