Rescue of cognitive and negative-like symptoms by chronic aripiprazole treatment in a 3-hit mouse model of neurodevelopmental disorder.

Introduction: 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 encompass the broad and heterogeneous symptom spectrum. The development of refined, translationally relevant models is therefore critical to advance both mechanistic understanding and therapeutic innovation. Methods: Here, we assessed in male and female mice the characterization of an innovative 3-hit mouse model that integrates genetic, environmental, and pharmacological risk factors, with a particular emphasis on the glutamatergic deficit hypothesis. The model combines: serine racemase deletion (reduced NMDA receptor co-agonist synthesis), maternal separation at postnatal day 9 (early-life stress), and subchronic phencyclidine exposure (NMDA receptor antagonism). Moreover, to assess the predictive validity of the model, a group of 3-hit mice was treated with chronic aripiprazole (1 mg/kg). Results: Behavioral analysis showed that 3-hit mice display a broad schizophrenia-like phenotype, marked by hyperlocomotion, memory deficits, impaired social recognition, social withdrawal, and apathy-like behavior. Importantly, chronic aripiprazole attenuated most of these alterations, underlying the predictive validity of the model. Discussion: By integrating multiple causal dimensions, this 3-hit combination provides a relevant way to induce a complex phenotype with schizophrenia-like behavioral keys, offering a new preclinical model to explore therapeutic strategies for schizophrenia profiles with cognitive and negative deficits.