Treatment strategy targeting 5-HT6R in an innovative animal model of schizophrenia

Schizophrenia (SCZ) is a frequent psychosis related to combination between genetic and environmental factors. To advance current treatments, it is important to improve animal models by considering its multifactorial etiology. Our study aimed to characterize an innovative 2-hit mouse model combining the deletion of serine racemase (genetic factor) associated with a maternal separation for 24h at post-natal day 9 (early stressing environmental factor), which both have been previously suggested to possibly drive SCZ-like symptoms. The face facility of this 2-hit model was assessed through behavioral experiments. Hence, male mice displayed an increase in locomotor activity possibly reflecting positive-like symptoms, working memory impairments illustrating cognitive deficits and recognition memory alterations that could underlie neophobia. The model was then used to investigate therapeutic interest of the 5-HT6R antagonist SB-271046 since beneficial effects of 5-HT6R blockade on memory and anxiety-like effects has been reported. Interestingly, sub-chronic (2 weeks) treatment with SB-271046 at 10mg/kg/day prevented the cognitive deficits, but not the hyperlocomotion symptom. Taken together, our results show that 1) this new multifactorial model displays an interesting phenotype for modelling SCZ and 2) the efficacy of the 5-HT6R antagonism strategy is limited and requires combination with antipsychotic drugs or physical activity to better counteract the deficits observed in our model that is under investigation.