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

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

1. Roman Tyzio1,2,*, 
2. Romain Nardou3,*, 
3. Diana C. Ferrari3,*, 
4. Timur Tsintsadze1,2,3, 
5. Amene Shahrokhi3,†,
6. Sanaz Eftekhari3,†, 
7. Ilgam Khalilov1,2, 
8. Vera Tsintsadze1,2, 
9. Corinne Brouchoud1,2, 
10. Genevieve Chazal1,2,
11. Eric Lemonnier4, 
12. Natalia Lozovaya1,2, 
13. Nail Burnashev1,2, 
14. Yehezkel Ben-Ari1,2,3,‡

+Author Affiliations

1. ¹Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
2. ²UMR 901, Aix-Marseille University, Marseille, France.
3. ³Neurochlore, Campus scientific de Luminy, 163 route de Luminy, Marseille 13273, Cedex 09, France.
4. ⁴Laboratoire de Neurosciences de Brest EA4685, Brest, France.

1. ↵‡Corresponding author. E-mail: yehezkel.ben-ari@inserm.fr

• ABSTRACT
• EDITOR'S 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.

• ↵* These authors contributed equally to this work.
• ↵† On leave from Tehran University of Medical Sciences, Tehran, Iran.

• Received for publication 14 October 2013.
• Accepted for publication 10 December 2013.

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