Differential depletion of GluN2A induces heterogeneous schizophrenia-related phenotypes in miceResearch in context
Yi Lu,
Longyu Mu,
Justin Elstrott,
Chaoying Fu,
Cailu Sun,
Tonghui Su,
Xiaofan Ma,
Jia Yan,
Hong Jiang,
Jesse E. Hanson,
Yang Geng,
Yelin Chen
Affiliations
Yi Lu
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
Longyu Mu
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
Justin Elstrott
Department of Translational Imaging, Genentech Inc., South San Francisco, CA 94080, USA
Chaoying Fu
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China
Cailu Sun
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
Tonghui Su
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China
Xiaofan Ma
Department of Anaesthesiology, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, Shanghai 200011, China
Jia Yan
Department of Anaesthesiology, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, Shanghai 200011, China
Hong Jiang
Department of Anaesthesiology, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, Shanghai 200011, China
Jesse E. Hanson
Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA
Yang Geng
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; Corresponding author.
Yelin Chen
Interdisciplinary Research Centre on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, No.100 Haike Rd., Pudong New District, Shanghai 201210, China; Corresponding author.
Summary: Background: Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A’s expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. Methods: We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. Findings: Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. Interpretation: Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. Funding: This project received support from the Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02) awarded to Y.C. and the Natural Science Foundation of Shanghai (Grant No. 19ZR1468600 and 201409003800) awarded to G.Y.
