ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Rescue of cognitive and negative-like symptoms by chronic aripiprazole treatment in a 3-hit mouse model of neurodevelopmental disorder
Provisionally accepted
Imane Mouffok1,2Noa Roudaut1,2Cécile Chofflet1,2
Thomas Freret1,2
Michel Boulouard1,2
Valentine Bouet1,2*- 1Laboratoire COMETE, Caen, France
- 2Université de Caen Normandie, Caen, France
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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. 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 mode, a group of 3-hit mice was treated with chronic aripiprazole (1 mg/kg). 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, underlining the predictive validity of the model. 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.
Keywords: coat grooming, Glutamate, Multifactorial model, pharmacological models of schizophrenia, Phencyclidine, recognition memory, Selfcare, working memory
Received: 04 Dec 2025; Accepted: 30 Jan 2026.
Copyright: © 2026 Mouffok, Roudaut, Chofflet, Freret, Boulouard and Bouet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Valentine Bouet
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