Cl 动态平衡改变阻碍了智力障碍小鼠模型前脑 GABA 能中间神经元的迁移。
Altered Cl homeostasis hinders forebrain GABAergic interneuron migration in a mouse model of intellectual disability.
机构信息
Veneto Institute of Molecular Medicine, 35129 Padua, Italy.
Padova Neuroscience Center, 35129 Padova, Italy.
出版信息
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). doi: 10.1073/pnas.2016034118.
Impairments of inhibitory circuits are at the basis of most, if not all, cognitive deficits. The impact of OPHN1, a gene associate with intellectual disability (ID), on inhibitory neurons remains elusive. We addressed this issue by analyzing the postnatal migration of inhibitory interneurons derived from the subventricular zone in a validated mouse model of ID (OPHN1 mice). We found that the speed and directionality of migrating neuroblasts were deeply perturbed in OPHN1 mice. The significant reduction in speed was due to altered chloride (Cl) homeostasis, while the overactivation of the OPHN1 downstream signaling pathway, RhoA kinase (ROCK), caused abnormalities in the directionality of the neuroblast progression in mutants. Blocking the cation-Cl cotransporter KCC2 almost completely rescued the migration speed while proper directionality was restored upon ROCK inhibition. Our data unveil a strong impact of OPHN1 on GABAergic inhibitory interneurons and identify putative targets for successful therapeutic approaches.
抑制性回路的损伤是大多数（如果不是全部）认知缺陷的基础。与智力障碍（ID）相关的基因 OPHN1 对抑制性神经元的影响仍不清楚。我们通过分析 ID （OPHN1 小鼠）验证模型中源自侧脑室下区的抑制性中间神经元的出生后迁移来解决这个问题。我们发现 OPHN1 小鼠中转录的神经母细胞的迁移速度和方向发生了严重的紊乱。速度的显著降低是由于氯离子（Cl）稳态的改变，而 OPHN1 下游信号通路 RhoA 激酶（ROCK）的过度激活导致了突变体中神经母细胞行进方向的异常。阻断阳离子-Cl 共转运蛋白 KCC2 几乎可以完全挽救迁移速度，而 ROCK 抑制则恢复了正确的方向。我们的数据揭示了 OPHN1 对 GABA 能抑制性中间神经元的强烈影响，并确定了成功治疗方法的潜在靶点。
Zotero 插件