Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring

We report that the oxytocin-mediated neuroprotective γ-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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2014-02, Vol.343 (6171), p.675-679
Main Authors: Tyzio, Roman, Nardou, Romain, Ferrari, Diana C., Tsintsadze, Timur, Shahrokhi, Amene, Eftekhari, Sanaz, Khalilov, Ilgam, Tsintsadze, Vera, Brouchoud, Corinne, Chazal, Genevieve, Lemonnier, Eric, Lozovaya, Natalia, Burnashev, Nail, Ben-Ari, Yehezkel
Format: Article
Language:English
Subjects:
Animal models
Animals
Autism
Autistic disorder
Autistic Disorder - chemically induced
Autistic Disorder - genetics
Autistic Disorder - metabolism
Behavior, Animal
Behavioral neuroscience
Bumetanide - administration & dosage
Cellular Biology
Chlorides
Chlorides - metabolism
Cytoprotection
Developmental biology
Disease Models, Animal
Female
Fragile X Mental Retardation Protein - genetics
gamma-Aminobutyric Acid - metabolism
Inhibition
Life Sciences
Maternal-Fetal Exchange
Mice
Neurons
Obstetric delivery
Oxytocin - metabolism
Parturition
Pathogenesis
Pregnancy
Pretreatment
Rats
Rodents
Santé publique et épidémiologie
Valproic Acid - pharmacology
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Summary:We report that the oxytocin-mediated neuroprotective γ-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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1247190