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Open AccessArticle

Comprehensive Analysis of GABAA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease

1
Synaptic Metabolism Lab, Neurology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu and CIBERER, 08950 Barcelona, Spain
2
Genetics Department, Institut Pediàtric de Recerca Hospital Sant Joan de Déu, 08950 Barcelona, Spain
3
Neurology Department, Institut Pediàtric de Recerca Hospital Sant Joan de Déu, and CIBERER, 08950 Barcelona, Spain
4
Neural Development Lab, Departament de Patologia i Terapèutica Experimental, Institut de Neurociènces, Universitat de Barcelona, IDIBELL, 08950 Barcelona, Spain
5
Bellvitge Biomedical Research Institute, Neuropharmacology and Pain Unit, University of Barcelona, 08950 Barcelona, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(2), 518; https://doi.org/10.3390/ijms21020518
Received: 30 November 2019 / Revised: 3 January 2020 / Accepted: 10 January 2020 / Published: 14 January 2020
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid (GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between MeCP2 and GABAA.-A1 receptor expression, emphasizing the time dependence of such relationship. For this, we analyzed the expression of the ionotropic receptor subunit in different MeCP2 gene-dosage and developmental conditions, in cells lines, and in primary cultured neurons, as well as in different developmental stages of a Rett mouse model. Further, RNAseq and systems biology analysis was performed from post-mortem brain biopsies of Rett patients. We observed that the modulation of the MeCP2 expression in cellular models (both Neuro2a (N2A) cells and primary neuronal cultures) revealed a MeCP2 positive effect on the GABAA.-A1 receptor subunit expression, which did not occur in other proteins such as KCC2 (Potassium-chloride channel, member 5). In the Mecp2+/− mouse brain, both the KCC2 and GABA subunits expression were developmentally regulated, with a decreased expression during the pre-symptomatic stage, while the expression was variable in the adult symptomatic mice. Finally, the expression of the gamma-aminobutyric acid (GABA) receptor-related synaptic proteins from the postmortem brain biopsies of two Rett patients was evaluated, specifically revealing the GABA A1R subunit overexpression. The identification of the molecular changes along with the Rett syndrome prodromic stages strongly endorses the importance of time frame when addressing this disease, supporting the need for a neurotransmission-targeted early therapeutic intervention.
Keywords: Rett syndrome; GABA; autism; GABA-A1R; KCC2; RNAseq Rett syndrome; GABA; autism; GABA-A1R; KCC2; RNAseq
MDPI and ACS Style

Oyarzabal, A.; Xiol, C.; Castells, A.A.; Grau, C.; O’Callaghan, M.; Fernández, G.; Alcántara, S.; Pineda, M.; Armstrong, J.; Altafaj, X.; García-Cazorla, A. Comprehensive Analysis of GABAA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease. Int. J. Mol. Sci. 2020, 21, 518.

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