{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:33:28Z","timestamp":1793507608945,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,14]],"date-time":"2020-01-14T00:00:00Z","timestamp":1578960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/01159, PI16\/00851, PI15\/01082"],"award-info":[{"award-number":["PI15\/01159, PI16\/00851, PI15\/01082"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mi Princesa Rett","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and \u03b3-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+\/\u2212 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.<\/jats:p>","DOI":"10.3390\/ijms21020518","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T10:30:27Z","timestamp":1579084227000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Comprehensive Analysis of GABAA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease"],"prefix":"10.3390","volume":"21","author":[{"given":"Alfonso","family":"Oyarzabal","sequence":"first","affiliation":[{"name":"Synaptic Metabolism Lab, Neurology Department, Institut Pedi\u00e0tric de Recerca, Hospital Sant Joan de D\u00e9u and CIBERER, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Xiol","sequence":"additional","affiliation":[{"name":"Genetics Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-8562","authenticated-orcid":false,"given":"Alba Aina","family":"Castells","sequence":"additional","affiliation":[{"name":"Genetics Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Grau","sequence":"additional","affiliation":[{"name":"Synaptic Metabolism Lab, Neurology Department, Institut Pedi\u00e0tric de Recerca, Hospital Sant Joan de D\u00e9u and CIBERER, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"O\u2019Callaghan","sequence":"additional","affiliation":[{"name":"Neurology Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, and CIBERER, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guerau","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Genetics Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soledad","family":"Alc\u00e1ntara","sequence":"additional","affiliation":[{"name":"Neural Development Lab, Departament de Patologia i Terap\u00e8utica Experimental, Institut de Neuroci\u00e8nces, Universitat de Barcelona, IDIBELL, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Pineda","sequence":"additional","affiliation":[{"name":"Neurology Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, and CIBERER, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-9307","authenticated-orcid":false,"given":"Judith","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Genetics Department, Institut Pedi\u00e0tric de Recerca Hospital Sant Joan de D\u00e9u, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7595-0647","authenticated-orcid":false,"given":"Xavier","family":"Altafaj","sequence":"additional","affiliation":[{"name":"Bellvitge Biomedical Research Institute, Neuropharmacology and Pain Unit, University of Barcelona, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angels","family":"Garc\u00eda-Cazorla","sequence":"additional","affiliation":[{"name":"Synaptic Metabolism Lab, Neurology Department, Institut Pedi\u00e0tric de Recerca, Hospital Sant Joan de D\u00e9u and CIBERER, 08950 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrneurol.2016.186","article-title":"Clinical and biological progress over 50 years in Rett syndrome","volume":"13","author":"Leonard","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s12017-014-8295-9","article-title":"Rett syndrome and MeCP2","volume":"16","author":"Liyanage","year":"2014","journal-title":"Neuromol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s13023-016-0545-5","article-title":"Rett syndrome-biological pathways leading from MECP2 to disorder phenotypes","volume":"11","author":"Ehrhart","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.neubiorev.2014.01.011","article-title":"Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action","volume":"46","author":"Bedogni","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s11920-010-0097-7","article-title":"The role of MeCP2 in brain development and neurodevelopmental disorders","volume":"12","author":"Gonzales","year":"2010","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1002\/neu.10201","article-title":"The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells","volume":"55","author":"Jung","year":"2003","journal-title":"J. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41583-018-0006-3","article-title":"Rett syndrome: Insights into genetic, molecular and circuit mechanisms","volume":"19","author":"Ip","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.nbd.2009.05.001","article-title":"Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations","volume":"35","author":"Chapleau","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4137\/JCNSD.S14012","article-title":"Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains","volume":"6","author":"Kang","year":"2014","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1523\/JNEUROSCI.5966-09.2010","article-title":"Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate","volume":"30","author":"Maezawa","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/npp.2012.116","article-title":"The impact of MeCP2 loss- or gain-of-function on synaptic plasticity","volume":"38","author":"Na","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/hipo.22360","article-title":"Excitation\/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice","volume":"25","author":"Calfa","year":"2015","journal-title":"Hippocampus"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Duarte, S.T., Armstrong, J., Roche, A., Ortez, C., Perez, A., Maria del Mar, O.C., Pereira, A., Sanmart\u00ed, F., Ormaz\u00e1bal, A., and Artuch, R. (2013). Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068851"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrn2370","article-title":"GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition","volume":"9","author":"Jacob","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3389\/neuro.02.007.2008","article-title":"GABA(A) Receptor Dynamics and Constructing GABAergic Synapses","volume":"1","author":"Tretter","year":"2008","journal-title":"Front. Mol. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0166-2236(96)80023-3","article-title":"Which GABAA-receptor subtypes really occur in the brain?","volume":"19","author":"McKernan","year":"1996","journal-title":"Trends Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cicek, S.S. (2018). Structure-Dependent Activity of Natural GABA(A) Receptor Modulators. Molecules, 23.","DOI":"10.3390\/molecules23071512"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1006\/exnr.1999.7030","article-title":"Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome","volume":"156","author":"Blue","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.nbd.2017.09.006","article-title":"Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome","volume":"109","author":"Chen","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1152\/jn.00601.2009","article-title":"MeCP2 is required for normal development of GABAergic circuits in the thalamus","volume":"103","author":"Zhang","year":"2010","journal-title":"J. Neurophysiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1073\/pnas.1524013113","article-title":"KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome","volume":"113","author":"Tang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e14198","DOI":"10.7554\/eLife.14198","article-title":"Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome","volume":"5","author":"Ure","year":"2016","journal-title":"Elife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1042\/BST0380498","article-title":"Reversibility of functional deficits in experimental models of Rett syndrome","volume":"38","author":"Cobb","year":"2010","journal-title":"Biochem. So. Trans."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2914","DOI":"10.1172\/JCI78167","article-title":"MECP2 disorders: From the clinic to mice and back","volume":"125","author":"Lombardi","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"Consortium","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"El-Khoury, R., Panayotis, N., Matagne, V., Ghata, A., Villard, L., and Roux, J.-C. (2014). GABA and glutamate pathways are spatially and developmentally affected in the brain of Mecp2-deficient mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092169"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1523\/JNEUROSCI.4900-12.2014","article-title":"Loss of MeCP2 from forebrain excitatory neurons leads to cortical hyperexcitation and seizures","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e14199","DOI":"10.7554\/eLife.14199","article-title":"Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders","volume":"5","author":"Meng","year":"2016","journal-title":"Elife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3389\/fncel.2019.00048","article-title":"Reciprocal Regulation of KCC2 Trafficking and Synaptic Activity","volume":"13","author":"Heubl","year":"2019","journal-title":"Front. Cell Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1038\/s41467-017-01749-0","article-title":"GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl(-)-sensitive WNK1 kinase","volume":"8","author":"Heubl","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41422","DOI":"10.1074\/jbc.M401354200","article-title":"Analysis of the set of GABA(A) receptor genes in the human genome","volume":"279","author":"Simon","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Enoch, M.-A., Baghal, B., Yuan, Q., and Goldman, D. (2013). A factor analysis of global GABAergic gene expression in human brain identifies specificity in response to chronic alcohol and cocaine exposure. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064014"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s42003-019-0413-7","article-title":"Human brain transcriptome analysis finds region- and subject-specific expression signatures of GABAAR subunits","volume":"2","author":"Sequeira","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1097\/FBP.0b013e32830c3645","article-title":"Mouse models of Rett syndrome: From behavioural phenotyping to preclinical evaluation of new therapeutic approaches","volume":"19","author":"Ricceri","year":"2008","journal-title":"Behav. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fnmol.2019.00173","article-title":"Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function","volume":"12","author":"Moore","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eaau0164","DOI":"10.1126\/scitranslmed.aau0164","article-title":"Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice","volume":"11","author":"Tang","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9276","DOI":"10.1038\/s41598-019-45635-9","article-title":"Early alterations in a mouse model of Rett syndrome: The GABA developmental shift is abolished at birth","volume":"9","author":"Lozovaya","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1038\/s41593-018-0270-6","article-title":"Characterization of human mosaic Rett syndrome brain tissue by single-nucleus RNA sequencing","volume":"21","author":"Renthal","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neubiorev.2019.05.013","article-title":"Rett syndrome before regression: A time window of overlooked opportunities for diagnosis and intervention","volume":"107","author":"Cosentino","year":"2019","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"103537","DOI":"10.1016\/j.jprot.2019.103537","article-title":"Brain protein changes in Mecp2 mouse mutant models: Effects on disease progression of Mecp2 brain specific gene reactivation","volume":"210","author":"Cortelazzo","year":"2020","journal-title":"J. Proteom."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9467819","DOI":"10.1155\/2017\/9467819","article-title":"Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome","volume":"2017","author":"Cortelazzo","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"480980","DOI":"10.1155\/2014\/480980","article-title":"Subclinical inflammatory status in Rett syndrome","volume":"2014","author":"Cortelazzo","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.biopsych.2017.05.028","article-title":"Rett-like Severe Encephalopathy Caused by a De Novo GRIN2B Mutation Is Attenuated by D-serine Dietary Supplement","volume":"83","author":"Soto","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/109065702760093843","article-title":"Spectrum of MECP2 mutations in Rett syndrome","volume":"6","author":"Bienvenu","year":"2002","journal-title":"Genet Test"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome","volume":"27","author":"Guy","year":"2001","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:43:00Z","timestamp":1760362980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/2\/518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,14]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21020518"],"URL":"https:\/\/doi.org\/10.3390\/ijms21020518","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,14]]}}}