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Free keywords:
Animals
Brain Stem/growth & development/*metabolism/physiopathology
Disease Models, Animal
Efferent Pathways/growth & development/metabolism/physiopathology
Excitatory Postsynaptic Potentials/genetics
Female
Genetic Predisposition to Disease/*genetics
Inhibitory Postsynaptic Potentials/genetics
Male
Methyl-CpG-Binding Protein 2/*genetics
Mice
Mice, Knockout
Neural Inhibition/genetics
Organ Culture Techniques
Patch-Clamp Techniques
Respiratory Center/growth & development/metabolism/physiopathology
Reticular Formation/growth & development/metabolism/physiopathology
Rett Syndrome/genetics/*metabolism/physiopathology
Signal Transduction/genetics
Synapses/*metabolism
Synaptic Transmission/genetics
gamma-Aminobutyric Acid/*metabolism
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.
