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

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

doi:10.1038/s41598-019-45635-9

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	9276
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-45635-9
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1038/s41598-019-45635-9

Cite this

Lozovaya, N., Nardou, R., Tyzio, R., Chiesa, M., Pons-Bennaceur, A., Eftekhari, S., Bui, T. T., Billon-Grand, M., Rasero, J., Bonifazi, P., Guimond, D., Gaiarsa, J. L., Ferrari, D. C., & Ben-Ari, Y. (2019). Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth. Scientific reports, 9(1), [9276]. https://doi.org/10.1038/s41598-019-45635-9

Lozovaya, N, Nardou, R, Tyzio, R, Chiesa, M, Pons-Bennaceur, A, Eftekhari, S, Bui, TT, Billon-Grand, M, Rasero, J, Bonifazi, P, Guimond, D, Gaiarsa, JL, Ferrari, DC & Ben-Ari, Y 2019, 'Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth', Scientific reports, vol. 9, no. 1, 9276. https://doi.org/10.1038/s41598-019-45635-9

@article{092ef4f1c6ef40a1bbe96664ab3040c0,

title = "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.",

author = "N. Lozovaya and R. Nardou and R. Tyzio and M. Chiesa and A. Pons-Bennaceur and S. Eftekhari and Bui, {T. T.} and M. Billon-Grand and J. Rasero and P. Bonifazi and D. Guimond and Gaiarsa, {J. L.} and Ferrari, {D. C.} and Y. Ben-Ari",

note = "Funding Information: We are grateful to C Dumon, R Cloarec, B Riffault, A Dufour, L-A Gouty-Colomer, V Matarazzo, F Michel, D Diabira, and A Fernandez for their contributions to some of the experiments, and N Burnashev for criticism. Financial support was provided by Neurochlore; Fondation Bettencourt Schueller; France{\textquoteright}s Agence Nationale de la Recherche (ANR-14-CE13-0021-01); and Fondation de France (no 2014-00052268). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41598-019-45635-9",

language = "English (US)",

volume = "9",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Early alterations in a mouse model of Rett syndrome

T2 - the GABA developmental shift is abolished at birth

AU - Lozovaya, N.

AU - Nardou, R.

AU - Tyzio, R.

AU - Chiesa, M.

AU - Pons-Bennaceur, A.

AU - Eftekhari, S.

AU - Bui, T. T.

AU - Billon-Grand, M.

AU - Rasero, J.

AU - Bonifazi, P.

AU - Guimond, D.

AU - Gaiarsa, J. L.

AU - Ferrari, D. C.

AU - Ben-Ari, Y.

N1 - Funding Information: We are grateful to C Dumon, R Cloarec, B Riffault, A Dufour, L-A Gouty-Colomer, V Matarazzo, F Michel, D Diabira, and A Fernandez for their contributions to some of the experiments, and N Burnashev for criticism. Financial support was provided by Neurochlore; Fondation Bettencourt Schueller; France’s Agence Nationale de la Recherche (ANR-14-CE13-0021-01); and Fondation de France (no 2014-00052268). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068057196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068057196&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-45635-9

DO - 10.1038/s41598-019-45635-9

M3 - Article

C2 - 31239460

AN - SCOPUS:85068057196

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 9276

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this