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.

Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons

“…An epigenetic study in a mouse model of RTT indicates that GABA A R ␤3 subunit expression is reduced in the cerebellum, and another molecular study confirmed down-regulation of the ␤3 subunit in the cerebellum (12,36). The ␣1 subunit in the frontal cortex and the ␣2 and ␣4 subunits in the ventrolateral medulla were also reduced in Mecp2-null mice (25). In LC neurons, our previous studies have shown that the postsynaptic GABA A and GABA B currents are both defective in Mecp2-null mice (10).…”

“…In mice, this is associated with multiple RTT-like phenotypes, including progressive motor dysfunction and abnormal breathing (15). In GABAergic neurons, impaired GABA synthesis and the consequent reduction in GABA quantum release have been found (10,15,25). In postsynaptic cells, there is a marked reduction in GABA A R density in the brain of RTT patients and Mecp2-null mice (34,35).…”

“…Indeed, several recent studies have shown that the breathing disorders of Mecp2-null mice can be alleviated by augmenting GABA synaptic inhibition (20,21). In contrast to the rich information of the synaptic GABA A Rs in RTT research (10,11,13,(22)(23)(24)(25), how the extrasynaptic GABA A Rs are affected by Mecp2 disruption remains unknown. The capability of these extrasynaptic GABA A Rs to reduce neuronal excitability without interrupting synaptic transmission suggests that these receptors may allow an alternative therapeutic intervention to RTT.…”

Correction of respiratory disorders in a mouse model of Rett syndrome

“…However, Medrihan et al (11) examined GABA synapses in the ventrolateral medulla of Mecp2 null males at postnatal day 7. Neither the discharge pattern relative to PN nor markers to more clearly define the area under study were used.…”

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

“…It is thus possible that de-regulated mTOR might adversely affect GABAergic synaptic activity. Notably, abnormal GABAergic transmission has been observed in Fmr1 knockout (KO) mice [134][135][136] and MeCP2 null mice [137,138]. In particular, Fmr1-KO mice have enhanced GABA-mediated synaptic transmission [134], while GABAergic synaptic transmission is greatly reduced in MeCP2 deficient mice [137,138].…”