Ito Takahiro, Yoshida Mikio, Aida Tomomi, Kushima Itaru, Hiramatsu Yuka, Ono Maiko, Yoshimi Akira, Tanaka Kohichi, Ozaki Norio, Noda Yukihiro
Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty and Graduate School of Pharmacy, Nagoya, Japan.
Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
J Neurochem. 2023 Apr;165(2):211-229. doi: 10.1111/jnc.15790. Epub 2023 Mar 15.
Astrotactin2 (ASTN2) regulates neuronal migration and synaptic strength through the trafficking and degradation of surface proteins. Deletion of ASTN2 in copy number variants has been identified in patients with schizophrenia, bipolar disorder, and autism spectrum disorder in copy number variant (CNV) analysis. Disruption of ASTN2 is a risk factor for these neurodevelopmental disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. However, the importance of ASTN2 in physiological functions remains poorly understood. To elucidate the physiological functions of ASTN2, we investigated whether deficiency of ASTN2 affects cognitive and/or emotional behaviors and neurotransmissions using ASTN2-deficient mice. Astn2 knockout (KO) mice produced by CRISPR/Cas9 technique showed no obvious differences in physical characteristics and circadian rhythm. Astn2 KO mice showed increased exploratory activity in a novel environment, social behavior and impulsivity, or decreased despair-, anxiety-like behaviors and exploratory preference for the novel object. Some behavioral abnormalities, such as increased exploratory activity and impulsivity, or decreased exploratory preference were specifically attenuated by risperidone, but not by haloperidol. While, the both drugs did not affect any emotion-related behavioral abnormalities in Astn2 KO mice. Dopamine contents were decreased in the striatum, and serotonin or dopamine turnover were increased in the striatum, nucleus accumbens, and amygdala of Astn2 KO mice. In morphological analyses, thinning of neural cell layers in the hippocampus, reduction of neural cell bodies in the prefrontal cortex, and decrease in spine density and PSD95 protein in both tissues were observed in Astn2 KO mice. The present findings suggest that ASTN2 deficiency develops some emotional or cognitive impairments related to monoaminergic dysfunctions and abnormal neuronal morphogenesis with shrinkage of neuronal soma. ASTN2 protein may contribute to the pathogenic mechanism and symptom onset of mental disorders.
Astrotactin2（ASTN2）通过表面蛋白的运输和降解来调节神经元迁移和突触强度。在精神分裂症、双相情感障碍和自闭症谱系障碍患者的拷贝数变异（CNV）分析中，已鉴定出拷贝数变异导致的ASTN2缺失。ASTN2功能破坏是这些神经发育障碍的危险因素，包括精神分裂症、双相情感障碍、自闭症谱系障碍和注意力缺陷多动障碍。然而，ASTN2在生理功能中的重要性仍知之甚少。为了阐明ASTN2的生理功能，我们使用ASTN2基因缺陷小鼠研究了ASTN2缺乏是否会影响认知和/或情绪行为及神经传递。通过CRISPR/Cas9技术产生的Astn2基因敲除（KO）小鼠在身体特征和昼夜节律上没有明显差异。Astn2 KO小鼠在新环境中表现出探索活动增加、社交行为和冲动性增加，或绝望样、焦虑样行为和对新物体的探索偏好降低。一些行为异常，如探索活动增加和冲动性增加，或探索偏好降低，可被利培酮特异性减轻，但氟哌啶醇则无此作用。同时，这两种药物均不影响Astn2 KO小鼠的任何与情绪相关的行为异常。Astn2 KO小鼠纹状体中的多巴胺含量降低，纹状体、伏隔核和杏仁核中的血清素或多巴胺周转率增加。在形态学分析中，Astn2 KO小鼠的海马神经细胞层变薄、前额叶皮质神经细胞体减少，且这两个组织中的棘突密度和PSD95蛋白均减少。目前的研究结果表明，ASTN2缺乏会导致一些与单胺能功能障碍和神经元形态异常及神经元胞体萎缩相关的情绪或认知障碍。ASTN2蛋白可能参与精神障碍的致病机制和症状发作。
