期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016034118
关键词
OPHN1; intellectual disability; Cl homeostasis; 2P imaging; interneuron migration
资金
- Telethon [GGP11116, GGP19281]
- Ministero dell'Istruzione, dell'Universita e della Ricerca-Consiglio Nazionale delle Ricerche Nanomax
The study revealed a strong impact of the OPHN1 gene on inhibitory interneurons migration in mice, with reduced speed and disturbed directionality. Disruption in chloride homeostasis and overactivation of the ROCK signaling pathway were identified as underlying mechanisms. Targeting these pathways could potentially lead to successful therapeutic approaches for cognitive deficits associated with OPHN1 mutations.
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(-/y) mice). We found that the speed and directionality of migrating neuroblasts were deeply perturbed in OPHN1(-/y) 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.
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