Abstract
Schizophrenia is a devastating mental disorder of neurodevelopmental origin, which affects ~1% of the population worldwide and represents a major socio-economic burden. It is characterized by a broad pattern of cognitive symptoms, including decreased attention, impaired memory, inaptitude to solve problems and alterations in social cognition. These deficits are poorly controlled by currently available antipsychotics which mainly reduce positive symptoms and, to a lesser extent, negative symptoms. Although improving symptomatic treatments remains an important goal, progress in disease management will likely require shift to novel modes of intervention initiated at an early stage of the disease in high-risk patients. Our team previously demonstrated that a sustained non-physiological activation of mammalian Target Of Rapamycin (mTOR) elicited by 5-HT6 receptors in the prefrontal cortex mediates deficits in social cognition and episodic memory in two rodent developmental models of schizophrenia. Here, we propose a novel disease modifier strategy to prevent emergence of cognitive deficits at the adult stage, in the neonatal phencyclidine model of schizophrenia. This strategy is based on the early blockade of 5-HT6 receptor-operated mTOR signaling during adolescence. We showed that early administration of a 5-HT6 receptor antagonist prevents the overactivation of prefrontal cortical mTOR at the adult stage and the associated cognitive deficits as well as the alterations of synaptic transmission and modifications of intrinsic properties of layer V of pyramidal neurons. This study demonstrates the interest of repositioning 5-HT6 receptor antagonists, which have shown good tolerance, as disease modifiers to alter the course of schizophrenia and prevent the emergence of cognitive deficits at early adulthood in at-risk individuals.