RESCUE OF COGNITIVE AND NEGATIVE-LIKE SYMPTOMS BY CHRONIC ARIPIPRAZOLE TREATMENT IN A 3-HIT MOUSE MODEL OF SCHIZOPHRENIA

Cognitive and negative symptoms remain among the most disabling features of schizophrenia but are still poorly addressed by existing antipsychotics. Advances in therapeutic development are hampered by the lack of preclinical models that adequately reflect the disorder’s multifactorial etiology, and by their limited ability to capture the full heterogeneous symptom spectrum. The development of refined, translationally relevant, animal models is therefore critical to understand the disease and improve therapeutic innovation. Here, we characterized a novel multifactorial mouse model that combines genetic, early and late risk factors (3-hit). Behavioral assessment in 3-hit mice revealed hyperlocomotion, memory deficits, impaired social recognition, social withdrawal, and apathy-like behavior. Moreover, we showed that chronic aripiprazole attenuated most of these effects. The model therefore gathers a face validity reflecting a broad schizophrenia-like phenotype and a predictive validity relevant for schizophrenia. By integrating multiple causal dimensions, this 3-hit construction provides an interesting way to induce a complex phenotype with schizophrenia-like behavioral hallmarks, offering a new preclinical model to explore therapeutic strategies for schizophrenia profiles with cognitive and negative deficits.