2025-05-27 イェール大学
イェール大学医学部の研究チームは、TRIO遺伝子の異なる変異が、知的障害、自閉スペクトラム症(ASD)、統合失調症、双極性障害などの神経発達障害にどのように影響を与えるかを明らかにしました。TRIOは細胞の骨格構造を制御するタンパク質群をコードしており、これらの変異が脳の構造や機能、行動に異なる影響を及ぼすことが示されました。
研究では、ASDに関連するK1431M変異、統合失調症に関連するK1918X変異、双極性障害に関連するM2145T変異を持つマウスを用いて、脳の大きさ、行動、神経活動を比較しました。その結果、K1431MおよびK1918X変異を持つマウスは、通常のマウスやM2145T変異を持つマウスよりも脳が小さいことが確認されました。これらの変異は、脳の発達や機能に異なる影響を与えることが示唆され、将来的な個別化治療の開発に貢献する可能性があります。
<関連情報>
- https://medicine.yale.edu/news-article/understanding-one-genes-role-in-different-neurodevelopmental-disorders/
- https://elifesciences.org/reviewed-preprints/103620#x673976253
神経発達障害に関連するTRIO変異体のヘテロ接合体は、マウスの行動、神経細胞の発達、シナプス伝達において明確な欠損をもたらす Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice
Yevheniia Ishchenko,Amanda T Jeng,Shufang Feng,Timothy Nottoli,Cindy Manriquez-Rodriguez,Khanh K Nguyen,Melissa G Carrizales,Matthew J Vitarelli,Ellen E Corcoran,Anthony J Koleske,…
eLife Published:May 7, 2025
DOI:https://doi.org/10.7554/eLife.103620.2
Abstract
Genetic variants in TRIO are associated with neurodevelopmental disorders (NDDs) including schizophrenia (SCZ), autism spectrum disorder (ASD) and intellectual disability. TRIO uses its two guanine nucleotide exchange factor (GEF) domains to activate GTPases (GEF1: Rac1 and RhoG; GEF2: RhoA) that control neuronal development and connectivity. It remains unclear how discrete TRIO variants differentially impact these neurodevelopmental events. Here, we investigate how heterozygosity for NDD-associated Trio variants – +/K1431M (ASD), +/K1918X (SCZ), and +/M2145T (bipolar disorder, BPD) – impact mouse behavior, brain development, and synapse structure and function. Heterozygosity for different Trio variants impacts motor, social, and cognitive behaviors in distinct ways that model clinical phenotypes in humans. Trio variants differentially impact head and brain size, with corresponding changes in dendritic arbors of motor cortex layer 5 pyramidal neurons (M1 L5 PNs). Although neuronal structure was only modestly altered in the Trio variant heterozygotes, we observe significant changes in synaptic function and plasticity. We also identified distinct changes in glutamate synaptic release in +/K1431M and +/M2145T cortico-cortical synapses. The TRIO K1431M GEF1 domain has impaired ability to promote GTP exchange on Rac1, but +/K1431M mice exhibit increased Rac1 activity, associated with increased levels of the Rac1 GEF Tiam1. Acute Rac1 inhibition with NSC23766 rescued glutamate release deficits in +/K1431M variant cortex. Our work reveals that discrete NDD-associated Trio variants yield overlapping but distinct phenotypes in mice, demonstrates an essential role for Trio in presynaptic glutamate release, and underscores the importance of studying the impact of variant heterozygosity in vivo.
