A New Three-Hit Mouse Model of Neurodevelopmental Disorder with Cognitive Impairments and Persistent Sociability Deficits.

Abstract

Cognitive deficits and negative symptoms associated with schizophrenia are poorly managed by current antipsychotics. In order to develop effective treatments, refining animal models of neurodevelopmental disorders is essential. To address their multifactorial etiology, we developed a new three-hit mouse model based on the hypoglutamatergic hypothesis of the pathology combined with early stress, offering strong construct validity. Thus, a genetic susceptibility (serine racemase deletion) was associated with an early environmental stress (24 h maternal separation at 9 days of age) and a further pharmacological treatment with phencyclidine (PCP, a glutamate receptor antagonist treatment, 10 mg/kg/day, from 8 to 10 weeks of age). The face validity of this model was assessed in female mice 1 and 6 weeks after the end of PCP treatment by a set of behavioral experiments investigating positive- and negative-like symptoms and cognitive deficits. Our results showed that the three-hit mice displayed persistent hyperlocomotion (positive-like symptoms) and social behavior impairment deficits (negative-like symptoms) but non-persistent spatial working memory deficits (cognitive symptoms). Our work confirms the usefulness of a three-hit combination to model, particularly for negative-like symptoms associated with schizophrenia and other psychiatric disorders. The model therefore gathers powerful construct and face validities and supports an involvement of glutamate dysfunction in behavioral symptoms.