Mechanism of region-specific neocortical malformation relevant to autism spectrum disorder

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06477
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: The University of Tokyo
• Principal Investigator: Kawaguchi Daichi 東京大学, 大学院薬学系研究科(薬学部), 助教 (70549518)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 脳・神経 / 発生・分化 / 自閉症 / 大脳新皮質 / 前頭前野

Outline of Final Research Achievements

Mechanisms of autism pathogenesis remain to be elucidated. Previous reports have shown that transient overgrowth in specific regions of neocortex is observed in autistic children. However, the mechanisms responsible for the region-specific cortical overgrowth remain largely unknown. In this study, we aimed to elucidate the mechanisms responsible for the autism-related cortical overgrowth. We developed and analyzed a mouse model of rostral cortex overgrowth, and the results suggest that abnormalities in the early embryonic period may be the cause of region-specific cortical overgrowth and autistic-like behaviors. In the enlarged cortical region, the balance of neuronal activity between excitatory and inhibitory neurons (E/I balance) was impaired. Furthermore, we found that gene expression profile in the enlarged brain region was different between wild-type and mice with rostral cortical overgrowth.

Free Research Field

神経発生生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、脳局所肥大モデルマウスにおいて興奮性ニューロンと抑制性ニューロンの活動バランス（E/Iバランス）の異常が見られた。E/Iバランスの異常は自閉症患者においても観察されており、肥大が原因となって活動異常が起こっている可能性が示唆された。また、脳局所肥大を伴う自閉症の発症メカニズムの一旦として、胎生期の局所的遺伝子変化が重要な役割を果たす可能性が示唆された。これまでの研究では、生後の自閉症症状を担う分子メカニズムが主に解析されてきたが、本研究により胎生期の異常が重要であるという可能性が新たに考えられた。