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Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.

ABSTRACT: Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2-/y mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutamatergic/GABAergic PSCs ratio is enhanced, hyper-synchronized activity is present and metabotropic long-term depression (LTD) is impacted. One day before delivery, maternal administration of the NKCC1 chloride importer antagonist bumetanide restored these parameters but not respiratory or weight deficits, nor the onset of mortality. Results suggest that birth is a critical period in RTT with important alterations that can be attenuated by bumetanide raising the possibility of early treatment of the disorder.

SUBMITTER: Lozovaya N

PROVIDER: S-EPMC6592949 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.

Lozovaya N N Nardou R R Tyzio R R Chiesa M M Pons-Bennaceur A A Eftekhari S S Bui T-T TT Billon-Grand M M Rasero J J Bonifazi P P Guimond D D Gaiarsa J-L JL Ferrari D C DC Ben-Ari Y Y

Scientific reports 20190625 1

Genetic mutations of the Methyl-CpG-binding protein-2 (MECP2) gene underlie Rett syndrome (RTT). Developmental processes are often considered to be irrelevant in RTT pathogenesis but neuronal activity at birth has not been recorded. We report that the GABA developmental shift at birth is abolished in CA3 pyramidal neurons of Mecp2<sup>-/y</sup> mice and the glutamatergic/GABAergic postsynaptic currents (PSCs) ratio is increased. Two weeks later, GABA exerts strong excitatory actions, the glutama ...[more]

PMID: 31239460

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Project description:Early development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT.Developmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher's Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA).Early developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3' truncations tended to have better developmental outcomes.Early developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT.This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.

Dataset Information

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.

Publications

Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.

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