Altered Cl⁻ homeostasis hinders forebrain GABAergic interneuron migration in a mouse model of intellectual disability

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-01, Vol.118 (2), p.1-12
• Main Authors: Maset, Andrea, Galla, Luisa, Francia, Simona, Cozzolino, Olga, Capasso, Paola, Goisis, Rosa Chiara, Losi, Gabriele, Lombardo, Angelo, Ratto, Gian Michele, Lodovichi, Claudia
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Brain; Cell Movement - physiology; Chlorides - metabolism; Chlorides - physiology; Coding; Cognitive ability; Cortex (somatosensory); Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Forebrain; GABAergic Neurons - metabolism; GABAergic Neurons - physiology; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Hippocampus; Homeostasis; Intellectual disabilities; Intellectual Disability - metabolism; Intellectual Disability - physiopathology; Interneurons - metabolism; Interneurons - physiology; Male; Mice; Models, Animal; Neural networks; Neural Stem Cells - metabolism; Neurogenesis; Nuclear Proteins - metabolism; Prosencephalon - metabolism; Retina; rhoA GTP-Binding Protein - metabolism; Signal Transduction; Spatial discrimination; Visual cortex; Visual field; Visual fields; Visual stimuli; Visual system; γ-Aminobutyric acid
• ISSN: 0027-8424; 1091-6490
• 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−/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.