5-HT6 receptor-operated mTOR signaling as a target for disease modifiers to prevent onset of cognitive deficits in schizophrenia. – StopSero6TOR

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 severely compromise the social and professional integration of patients and their quality of life. Cognitive symptoms are the earlier symptoms observed and are predictive of the risk of transition to schizophrenia. They are poorly controlled by currently available antipsychotics (dopamine D2 and serotonin 5-HT2A receptor antagonists), which mainly reduce positive symptoms (delusions and hallucinations) and, to a lesser extent, negative symptoms (e.g. anhedonia, lack of motivation).

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. A critical time frame for such an early intervention aimed at altering the course of the disease is adolescence, when the brain is undergoing a major structural and functional reorganization, including sprouting and pruning of synapses, changes in neurotransmitter concentrations and in their receptor levels in brain areas essential for cognitive functions such as the prefrontal cortex.

Among the targets currently under investigation to alleviate cognitive deficits of schizophrenia, the serotonin 5-HT6 receptor holds special promise. 5-HT6 receptors are expressed at early stage of brain development and control key neurodevelopmental processes such as neuronal migration and neurite growth. Highest receptor densities are found in brain regions involved in mnemonic functions and 5-HT6 receptor blockade alleviates deficits in several rodent models of cognitive impairment, including developmental models of schizophrenia. In an effort to identify signalling mechanisms underlying modulation of cognition by 5-HT6 receptor, we 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.

In light of these results and previous findings, which identified mTOR as a critical signalling node involved in the control of neural development and cognition, the StopSero6TOR project aims at proposing a novel disease modifier strategy to prevent emergence of cognitive deficits at the adult stage and conversion to schizophrenia in at-risk subjects. This strategy is based on early blockade of 5-HT6 receptor-operated mTOR signalling during adolescence. It will be evaluated in two complementary developmental models of schizophrenia of high translational value, mice treated at the neonatal stage with phencyclidine (PCP, pharmacological model) and Disc1-L100P mutant mice (genetic model). These models recapitulate in mature animals certain cognitive and other behavioural changes characteristic of schizophrenia.

The relevance of the proposed strategy is supported by a convergent set of preliminary data obtained in the neonatal PCP model, which showed that early administration of a 5-HT6 receptor antagonist during adolescence abolishes the overactivation of prefrontal cortical mTOR at the adult stage, rescues the deficit in novel object discrimination and compensates the associated alteration of GABAergic transmission in prefrontal cortex.

The StopSero6TOR project constitutes a unique opportunity to reposition 5-HT6 receptor antagonists, currently in clinical trials as symptomatic treatments of cognitive symptoms in a wide range of CNS disorders, as disease modifiers to alter the course of schizophrenia and prevent the emergence of cognitive deficits at early adulthood in at-risk individuals.