Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring

Roman Tyzio; Romain Nardou; Diana C. Ferrari; Timur Tsintsadze; Amene Shahrokhi; Sanaz Eftekhari; Ilgam Khalilov; Vera Tsintsadze; Corinne Brouchoud; Genevieve Chazal; Eric Lemonnier; Natalia Lozovaya; Nail Burnashev; Yehezkel Ben-Ari

doi:10.1126/science.1247190

Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring

Roman Tyzio, Romain Nardou, Diana C. Ferrari, Timur Tsintsadze, Amene Shahrokhi, Sanaz Eftekhari, Ilgam Khalilov, Vera Tsintsadze, Corinne Brouchoud, Genevieve Chazal, Eric Lemonnier, Natalia Lozovaya, Nail Burnashev, Yehezkel Ben-Ari

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

Abstract

We report that the oxytocin-mediated neuroprotective g-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Original language	English (US)
Pages (from-to)	675-679
Number of pages	5
Journal	Science
Volume	343
Issue number	6171
DOIs	https://doi.org/10.1126/science.1247190
State	Published - 2014
Externally published	Yes

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Tyzio, R., Nardou, R., Ferrari, D. C., Tsintsadze, T., Shahrokhi, A., Eftekhari, S., Khalilov, I., Tsintsadze, V., Brouchoud, C., Chazal, G., Lemonnier, E., Lozovaya, N., Burnashev, N., & Ben-Ari, Y. (2014). Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science, 343(6171), 675-679. https://doi.org/10.1126/science.1247190

Tyzio, R, Nardou, R, Ferrari, DC, Tsintsadze, T, Shahrokhi, A, Eftekhari, S, Khalilov, I, Tsintsadze, V, Brouchoud, C, Chazal, G, Lemonnier, E, Lozovaya, N, Burnashev, N & Ben-Ari, Y 2014, 'Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring', Science, vol. 343, no. 6171, pp. 675-679. https://doi.org/10.1126/science.1247190

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title = "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring",

abstract = "We report that the oxytocin-mediated neuroprotective g-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in na{\"i}ve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.",

author = "Roman Tyzio and Romain Nardou and Ferrari, {Diana C.} and Timur Tsintsadze and Amene Shahrokhi and Sanaz Eftekhari and Ilgam Khalilov and Vera Tsintsadze and Corinne Brouchoud and Genevieve Chazal and Eric Lemonnier and Natalia Lozovaya and Nail Burnashev and Yehezkel Ben-Ari",

year = "2014",

doi = "10.1126/science.1247190",

language = "English (US)",

volume = "343",

pages = "675--679",

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AU - Tyzio, Roman

AU - Nardou, Romain

AU - Ferrari, Diana C.

AU - Tsintsadze, Timur

AU - Shahrokhi, Amene

AU - Eftekhari, Sanaz

AU - Khalilov, Ilgam

AU - Tsintsadze, Vera

AU - Brouchoud, Corinne

AU - Chazal, Genevieve

AU - Lemonnier, Eric

AU - Lozovaya, Natalia

AU - Burnashev, Nail

AU - Ben-Ari, Yehezkel

PY - 2014

Y1 - 2014

N2 - We report that the oxytocin-mediated neuroprotective g-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

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Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring

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