Abstract
Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid (GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between MeCP2 and GABAA.-A1 receptor expression, emphasizing the time dependence of such relationship. For this, we analyzed the expression of the ionotropic receptor subunit in different MeCP2 gene-dosage and developmental conditions, in cells lines, and in primary cultured neurons, as well as in different developmental stages of a Rett mouse model. Further, RNAseq and systems biology analysis was performed from post-mortem brain biopsies of Rett patients. We observed that the modulation of the MeCP2 expression in cellular models (both Neuro2a (N2A) cells and primary neuronal cultures) revealed a MeCP2 positive effect on the GABAA.-A1 receptor subunit expression, which did not occur in other proteins such as KCC2 (Potassium-chloride channel, member 5). In the Mecp2+/− mouse brain, both the KCC2 and GABA subunits expression were developmentally regulated, with a decreased expression during the pre-symptomatic stage, while the expression was variable in the adult symptomatic mice. Finally, the expression of the gamma-aminobutyric acid (GABA) receptor-related synaptic proteins from the postmortem brain biopsies of two Rett patients was evaluated, specifically revealing the GABA A1R subunit overexpression. The identification of the molecular changes along with the Rett syndrome prodromic stages strongly endorses the importance of time frame when addressing this disease, supporting the need for a neurotransmission-targeted early therapeutic intervention.
Highlights
Rett syndrome (RTT; OMIM #312750) is a severe neurodevelopmental disorder characterized by a regression in the neurological development between 6 and 18 months following a normal early development
Based on previous reports supporting the contribution of GABAergic dysfunction in Rett syndrome progression and the alteration of the GABAA-A1 expression, we hypothesized that MeCP2 disturbance might directly affect the density of GABAA receptors, rather than such an altered expression being a secondary effect of an overall GABAergic dysfunction
We have observed a direct relationship between the MeCP2 altered expression and GABAergic receptors disruption, which is strongly dependent on the prodromic stage of the disease, angling the focus towards the time frame, which will be a key factor when looking for therapeutic options
Summary
Rett syndrome (RTT; OMIM #312750) is a severe neurodevelopmental disorder characterized by a regression in the neurological development between 6 and 18 months following a normal early development. MeCP2 is a nuclear protein that acts as an epigenetic regulator, controlling the expression of numerous genes (either as transcription activators or repressors) involved in several biological processes [3] Whilst it is a ubiquitous protein, MeCP2 is most highly expressed in the brain [2,4], most precisely in post mitotic neurons [5,6], and its deficiency results in a global neurodevelopment disturbance [7]. Rett syndrome has been associated with an aberrant expression of neurotransmitters, neuromodulators, transporters, and receptors [8,9,10,11]. The selective transport of Cl− when the GABAA receptors are activated hyperpolarizes the neuron, reducing its likelihood of starting an action potential [17]
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