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.