Dysfunction of cerebellar synapses in a mouse model of autism comorbid with ADHD and its application to the development of treatment

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07610
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Hisaoka Tomoko 和歌山県立医科大学, 医学部, 助教 (00398463)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 自閉症スペクトラム障害 / 注意欠如・多動性障害 / 小脳 / シナプス接着分子 / 免疫グロブリンスーパーファミリー

Outline of Final Research Achievements

We found that Kirrel3-knockout mice, a model of ASD comorbid with ADHD, exhibited disorganization of cerebellar pinceau synapse. Analysis of monoamine content in the brain of Kirrel3-knockout mice revealed altered dopamine content in the prefrontal cortex, which is connected to the cerebellum via ventral tegmental area. The cerebellum is the most consistent sites of abnormality in ASD. Impaired dopamine neurotransmission is well known to be the pathophysiology of ADHD. Therefore, the Kirrel3-knockout mouse is an ASD comorbid with ADHD model of both pathophysiological features. Further studies are required to elucidate the molecular mechanisms of impaired dopamine neurotransmission based on the cerebellar dysfunction using this model mouse. Based on the underlying molecular mechanisms, we aim to develop the new treatment for ASD comorbid with ADHD, such as the drug to control dopamine neurotransmission.

Free Research Field

神経発生学、神経組織学、行動生理学

Academic Significance and Societal Importance of the Research Achievements

注意欠如・多動性障害（ADHD）を伴う自閉症スペクトクトラム障害（ASD）様行動を示すKirrel3欠損マウスの小脳において、ピンスーシナプスの形成に異常が見られ、ADHD治療薬であるドーパミン系賦活薬の投与によりADHD様行動の増悪が見られたことから、この疾患の新たな病態を見いだした。これらの知見から、ADHDを伴うASDと小脳やドーパミン伝達神経回路との関連性をさらに解明することで、ADHD単独の病態とは異なるこの疾患の治療法の開発に役立つと考えられる。