Mouffok Imane, Lahogue Caroline, Cailly Thomas, Freret Thomas, Bouet Valentine, Boulouard Michel
Department of Health, Normandie Université, UNICAEN (Université de Caen Normandie), INSERM (Institut National de la Santé et de la Recherche Médicale), UMR (Unité Mixte de Recherche) 1075 COMETE, Campus 5, CYCERON, FHU (Fédération Hospitalo-Universitaire) A2M2P, CHU (Centre Hospitalo-Universitaire) Caen, 14000 Caen, France.
CERMN UR (Unité de Recherche) 4258, Campus 5, Université de Caen Normandie, 14000 Caen, France.
Brain Sci. 2024 Dec 20;14(12):1281. doi: 10.3390/brainsci14121281.
BACKGROUND/OBJECTIVES: 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.
背景/目的：目前的抗精神病药物对精神分裂症相关的认知缺陷和阴性症状治疗效果不佳。为了开发有效的治疗方法，完善神经发育障碍的动物模型至关重要。
为了解决其多因素病因，我们基于病理学的低谷氨酸能假说并结合早期应激，开发了一种新的三打击小鼠模型，具有很强的结构效度。因此，遗传易感性（丝氨酸消旋酶缺失）与早期环境应激（9日龄时母婴分离24小时）以及进一步用苯环利定（PCP，一种谷氨酸受体拮抗剂，10mg/kg/天，8至10周龄）进行药物治疗相结合。在PCP治疗结束后1周和6周，通过一组研究阳性和阴性样症状以及认知缺陷的行为实验，对该模型的表面效度进行了评估。
我们的结果表明，三打击小鼠表现出持续的运动亢进（阳性样症状）和社交行为障碍缺陷（阴性样症状），但空间工作记忆缺陷不持续（认知症状）。
我们的工作证实了三打击组合用于建模的有效性，特别是对于与精神分裂症和其他精神障碍相关的阴性样症状。因此，该模型具有强大的结构效度和表面效度，并支持谷氨酸功能障碍与行为症状有关。
