Combination of MAP6 deficit, maternal separation and MK801 in female mice: A 3-hit animal model of neurodevelopmental disorder with cognitive deficits.

Schizophrenia is a major psychiatric disease still lacking efficient treatment, particularly for cognitive deficits. To go further in research of new treatments that would encompass all the symptoms associated with this pathology, preclinical animal models need to be improved. To date, the aetiology of schizophrenia is unknown, but there is increasing evidence to highlight its multifactorial nature. We built a new neurodevelopmental mouse model gathering a triple factor combination (3-M): a genetic factor (partial deletion of MAP6 gene), an early stress (maternal separation) and a late pharmacological factor (MK801 administration, 0.05 mg/kg, i.p., daily for 5 days). The effects of each factor and of their combination were investigated on several behaviours including cognitive functions. While each individual factor induced slight deficits in one or another behavioural test, 3-M conditioning induces a wider phenotype with hyperlocomotion and cognitive deficits (working memory and social recognition). This study confirms the hypothesis that genetic, environmental and pharmacological factors, even if not deleterious by themselves, could act synergistically to induce a deleterious behavioural phenotype. It moreover encourages the use of such combined models to improve translational research on neurodevelopmental disorders.