SHANK3 基因突变与自闭症和精神分裂症有关,导致发育中老鼠大脑的树突棘动态发生共享和独特的变化。

SHANK3 Mutations Associated with Autism and Schizophrenia Lead to Shared and Distinct Changes in Dendritic Spine Dynamics in the Developing Mouse Brain.

机构信息

Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.

Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States.

出版信息

Neuroscience. 2023 Sep 15;528:1-11. doi: 10.1016/j.neuroscience.2023.07.024. Epub 2023 Jul 31.

Abstract

Autism Spectrum Disorders (ASD) and schizophrenia are distinct neurodevelopmental disorders that share certain symptoms and genetic components. Both disorders show abnormalities in dendritic spines, which are the main sites of excitatory synaptic inputs. Recent studies have identified the synaptic scaffolding protein Shank3 as a leading candidate gene for both disorders. Mutations in the SHANK3 gene have been linked to both ASD and schizophrenia; however, how patient-derived mutations affect the structural plasticity of dendritic spines during brain development is unknown. Here we use live two photon in vivo imaging to examine dendritic spine structural plasticity in mice with SHANK3 mutations associated with ASD and schizophrenia. We identified shared and distinct phenotypes in dendritic spine morphogenesis and plasticity in the ASD-associated InsG3680 mutant mice and the schizophrenia-associated R1117X mutant mice. No significant changes in dendritic arborization were observed in either mutant, raising the possibility that synaptic dysregulation may be a key contributor to the behavioral defects previously reported in these mice. These findings shed light on how patient-linked mutations in SHANK3 affect dendritic spine dynamics in the developing brain, which provides insight into the synaptic basis for the distinct phenotypes observed in ASD and schizophrenia.

摘要

自闭症谱系障碍(ASD)和精神分裂症是两种不同的神经发育障碍,它们具有某些共同的症状和遗传成分。这两种疾病都显示出树突棘的异常,树突棘是兴奋性突触输入的主要部位。最近的研究已经确定突触支架蛋白 Shank3 是这两种疾病的主要候选基因。SHANK3 基因突变与 ASD 和精神分裂症有关;然而,患者来源的突变如何影响大脑发育过程中树突棘的结构可塑性尚不清楚。在这里,我们使用活体双光子在体成像来研究与 ASD 和精神分裂症相关的 SHANK3 基因突变的小鼠中树突棘结构的可塑性。我们在与 ASD 相关的 InsG3680 突变小鼠和与精神分裂症相关的 R1117X 突变小鼠中鉴定出了树突棘形态发生和可塑性的共同和独特表型。在这两种突变体中均未观察到树突分支的明显变化,这表明突触失调可能是这些小鼠先前报道的行为缺陷的关键因素。这些发现揭示了 SHANK3 中的患者相关突变如何影响发育中大脑中的树突棘动力学,这为 ASD 和精神分裂症中观察到的不同表型的突触基础提供了线索。

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