2023-04-20 ミシガン大学
ミシガン大学の研究者たちは、ダウン症患者の遺伝子の一つであるDSCAMがマウスの神経発達に影響を与えることを発見した。この遺伝子は自閉症スペクトラム障害、双極性障害、難治性てんかんなどの人間の神経疾患にも関与している。
研究者は、この研究を通じて、DSCAMの過剰なコピーが、ダウン症マウスの大脳皮質で過剰な神経抑制を引き起こす原因であることを示した。
また、DSCAMの発現レベルを調節することが、ダウン症のシナプス機能の修復に有効である可能性があることが示唆された。
<関連情報>
- https://news.umich.edu/a-gene-involved-in-down-syndrome-puts-the-brakes-on-neurons-activity-in-mice-new-study-shows/
- https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002078
DSCAM遺伝子の三重化により、ダウン症マウスでは大脳新皮質のGABA作動性シナプスが過剰になることが判明 DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models
Hao Liu ,René N. Caballero-Florán ,Ty Hergenreder ,Tao Yang,Jacob M. Hull,Geng Pan,Ruonan Li,Macy W. Veling,Lori L. Isom,Kenneth Y. Kwan,Z. Josh Huang,Peter G. Fuerst,Paul M. Jenkins ,Bing Ye
PLOS BIOROGY Published: April 20, 2023
DOI:https://doi.org/10.1371/journal.pbio.3002078
Abstract
Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders.
