Laboratory for Multi-scale Biological Psychiatry, Center for Brain Science, RIKEN, 2-1 Hirosawa, Wako City, Saitama 351-0106, Japan.
Gunma University Graduate School of Medicine, Maebashi City, Gunma 371-8512, Japan.
Sci Adv. 2023 Jun 9;9(23):eade5973. doi: 10.1126/sciadv.ade5973.
Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were more abundant in the postmortem brains of patients with schizophrenia than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via XL spines.
人类遗传学强烈支持突触病在精神疾病中的作用。然而，将突触病理学与行为变化联系起来的跨尺度因果关系尚不清楚。为了解决这个问题，我们研究了突触输入对 SETD1A 和 DISC1 敲低的小鼠的树突、细胞和行为的影响，这些小鼠是精神分裂症的验证动物模型。这两种模型都表现出超大型（XL）突触的过度表达，这些突触引起超线性树突和体细胞整合，导致神经元放电增加。XL 棘突的出现概率与工作记忆呈负相关，而 XL 棘突生成的光预防恢复了工作记忆障碍。此外，精神分裂症患者的死后大脑中 XL 突触比匹配对照组更为丰富。我们的研究结果表明，工作记忆表现是精神症状的一个关键方面，它通过 XL 棘突来塑造扭曲的树突和体细胞整合。
