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2.
Front Cell Neurosci ; 16: 919493, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35936501

RESUMO

Dravet Syndrome (DS) is a rare autosomic encephalopathy with epilepsy linked to Nav1.1 channel mutations and defective GABAergic signaling. Effective therapies for this syndrome are lacking, urging a better comprehension of the mechanisms involved. In a recognized mouse model of DS, we studied GABA tonic current, a form of inhibition largely neglected in DS, in brain slices from developing mice before spontaneous seizures are reported. In neurons from the temporal cortex (TeCx) and CA1 region, GABA tonic current was reduced in DS mice compared to controls, while in the entorhinal cortex (ECx) it was not affected. In this region however allopregnanonole potentiation of GABA tonic current was reduced in DS mice, suggesting altered extrasynaptic GABAA subunits. Using THIP as a selective agonist, we found reduced δ subunit mediated tonic currents in ECx of DS mice. Unexpectedly in the dentate gyrus (DG), a region with high δ subunit expression, THIP-evoked currents in DS mice were larger than in controls. An immunofluorescence study confirmed that δ subunit expression was reduced in ECx and increased in DG of DS mice. Finally, considering the importance of neuroinflammation in epilepsy and neurodevelopmental disorders, we evaluated classical markers of glia activation. Our results show that DS mice have increased Iba1 reactivity and GFAP expression in both ECx and DG, compared to controls. Altogether we report that before spontaneous seizures, DS mice develop significant alterations of GABA tonic currents and glial cell activation. Understanding all the mechanisms involved in these alterations during disease maturation and progression may unveil new therapeutic targets.

3.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33376209

RESUMO

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.


Assuntos
Proteínas do Citoesqueleto/genética , Neurônios GABAérgicos/metabolismo , Proteínas Ativadoras de GTPase/genética , Deficiência Intelectual/metabolismo , Animais , Movimento Celular/fisiologia , Cloretos/metabolismo , Cloretos/fisiologia , Proteínas do Citoesqueleto/metabolismo , Neurônios GABAérgicos/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Homeostase , Deficiência Intelectual/fisiopatologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos , Modelos Animais , Células-Tronco Neurais/metabolismo , Neurogênese , Proteínas Nucleares/metabolismo , Prosencéfalo/metabolismo , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
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