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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.

Graphical Abstract

Abstract Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5‐HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5‐HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5‐HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5‐HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post‐weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5‐HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5‐HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.