title: GABA and glutamate pathways are spatially and developmentally affected in the brain of Mecp2-deficient mice.
abstract: Proper brain functioning requires a fine-tuning between excitatory and inhibitory neurotransmission, a balance maintained through the regulation and release of glutamate and GABA. Rett syndrome (RTT) is a rare genetic disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene affecting the postnatal brain development. Dysfunctions in the GABAergic and glutamatergic systems have been implicated in the neuropathology of RTT and a disruption of the balance between excitation and inhibition, together with a perturbation of the electrophysiological properties of GABA and glutamate neurons, were reported in the brain of the Mecp2-deficient mouse. However, to date, the extent and the nature of the GABA/glutamate deficit affecting the Mecp2-deficient mouse brain are unclear. In order to better characterize these deficits, we simultaneously analyzed the GABA and glutamate levels in Mecp2-deficient mice at 2 different ages (P35 and P55) and in several brain areas. We used a multilevel approach including the quantification of GABA and glutamate levels, as well as the quantification of the mRNA and protein expression levels of key genes involved in the GABAergic and glutamatergic pathways. Our results show that Mecp2-deficient mice displayed regional- and age-dependent variations in the GABA pathway and, to a lesser extent, in the glutamate pathway. The implication of the GABA pathway in the RTT neuropathology was further confirmed using an in vivo treatment with a GABA reuptake inhibitor that significantly improved the lifespan of Mecp2-deficient mice. Our results confirm that RTT mouse present a deficit in the GABAergic pathway and suggest that GABAergic modulators could be interesting therapeutic agents for this severe neurological disorder.
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France.
authors.forename: Rita
authors.initials: R
authors.lastname: El-Khoury
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France; Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panayotis
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Matagne
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Ghata
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR_S 910, Marseille, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Roux
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018755:GABA Agonists / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009557:Nipecotic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015518:Rett Syndrome / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D009435:Synaptic Transmission; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009557:Nipecotic Acids; D012333:RNA, Messenger; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000078308:Tiagabine