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.

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

“…Both GABA A and GABA B receptormediated postsynaptic inhibition are reduced, and the GABA release from presynaptic terminals is significantly low (10). Consistent with these observations, defects in the GABA A receptor (GABA A R) system are also found in other brain regions (11)(12)(13)(14). Selective deletion of the Mecp2 gene in GABAergic neurons recapitulates most RTT phenotypes in mice (15).…”

“…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.…”

Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1+/− patients and in foxg1+/− mice

“…Other studies have also found a reduction in GAD1 and GAD2 levels in post-mortem tissue from schizophrenic and autistic patients 55, 56 . To further complicate the situation, another study on MeCP2-deficient mice after analyzing both the GABA and glutamate neurotransmitter levels together with the mRNA and protein levels of key GABAergic and glutamatergic synaptic proteins, showed how alterations of the GABAergic system may follow opposite directions depending on the age of the mice and on the brain region analyzed 57 . Similarly, opposite effects were also observed in the levels of excitatory synaptic markers in different brain areas of adult Grid1 KO animals, which accompanied a series of behavioral defects 58 .…”

MECP2 disorders: from the clinic to mice and back

“…A decrease in synaptic plasticity, or the ability of neurons to change their synaptic strength in response to activity, is also observed in many neuronal types (52)(53)(54). Abnormalities in neurotransmitter concentrations occur in KO mice (55)(56)(57)(58)(59) as well as in patients with Rett syndrome (60-62). Thus, the major human phenotypes of Rett syndrome are recapitulated in mice, allowing for functional disease dissection in this model system (Table 1).…”

“…The locomotor activity of treated animals, as measured by distance traveled in the open-field assay, doubled (56). KO animals also exhibit decreased GABA levels in some areas of their brains (57,131), and administration of the GABA reuptake inhibitor NO-711 resulted in a four-fold decrease in apnea frequency (132). Serotonin receptor agonists have also been successful in ameliorating the breathing abnormalities of KO animals (132,133).…”