2024-12-23 韓国基礎科学研究院(IBS)
<関連情報>
- https://www.ibs.re.kr/cop/bbs/BBSMSTR_000000000738/selectBoardArticle.do?nttId=25428&pageIndex=1&searchCnd=&searchWrd=
- https://www.nature.com/articles/s41380-024-02865-2
リチウムはDYRK1AノックインマウスにおいてASDに関連する神経細胞、シナプス、行動の表現型を正常化する Lithium normalizes ASD-related neuronal, synaptic, and behavioral phenotypes in DYRK1A-knockin mice
Junyeop Daniel Roh,Mihyun Bae,Hyosang Kim,Yeji Yang,Yeunkeum Lee,Yisul Cho,Suho Lee,Yan Li,Esther Yang,Hyunjee Jang,Hyeonji Kim,Hyun Kim,Hyojin Kang,Jacob Ellegood,Jason P. Lerch,Yong Chul Bae,Jin Young Kim & Eunjoon Kim
Molecular Psychiatry Published:05 December 2024
DOI:https://doi.org/10.1038/s41380-024-02865-2
Abstract
Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.
