title: Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome.
abstract: Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic gamma-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABA(A)-receptor subunits alpha2 and alpha4. Our data indicate that in the MeCP2 -/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.
authors.affiliation: Center for Physiology and Pathophysiology, Georg-August University of Göttingen, Göttingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Medrihan
authors.forename: E
authors.initials: E
authors.lastname: Tantalaki
authors.forename: G
authors.initials: G
authors.lastname: Aramuni
authors.forename: V
authors.initials: V
authors.lastname: Sargsyan
authors.forename: I
authors.initials: I
authors.lastname: Dudanova
authors.forename: M
authors.initials: M
authors.lastname: Missler
authors.forename: W
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D012125:Respiratory Center / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D012154:Reticular Formation / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D005680:gamma-Aminobutyric Acid