| Literature DB >> 33376209 |
Andrea Maset1,2,3, Luisa Galla3,4, Simona Francia1,5, Olga Cozzolino6,7, Paola Capasso8, Rosa Chiara Goisis3,4, Gabriele Losi3,4, Angelo Lombardo8,9, Gian Michele Ratto6,7, Claudia Lodovichi10,2,3,4.
Abstract
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.Entities:
Keywords: 2P imaging; Cl homeostasis; OPHN1; intellectual disability; interneuron migration
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Year: 2021 PMID： 33376209 PMCID： PMC7812749 DOI： 10.1073/pnas.2016034118
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205