Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring
Abstract
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.
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There is a prominent delay in the normal excitatory to inhibitory switch of GABA during postnatal development due to abnormally high levels of NKCC1 beyond P10 in Fmr1 mutant mice.
“In particular, there is a prominent delay in the normal excitatory to inhibitory switch of GABA during postnatal development due to abnormally high levels of NKCC1 beyond P10 in Fmr1 mutant mice 108,109 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [109]
Oxytocin treatment in the embryonic period suppresses GABA-mediated excitation in mice, and these effects were blocked by infusion of an OTR antagonist.
“Tyzio et al. (2014) showed that oxytocin treatment in the embryonic period suppresses GABA-mediated excitation in mice and that these effects were blocked by the infusion of an OTR antagonist (Tyzio et al. 2014).”
From A precision medicine approach to oxytocin trials (2017) · cites this paper as Tyzio et al. 2014
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- Authors
- 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.
- Affiliations
- Inserm (FR)
- Neurochlore (France) (FR)
- Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
- Laboratoire de Neurosciences de Brest EA4685, Brest, France.
- Corresponding author
- Tyzio, Roman
- Nardou, Romain
- Ferrari, Diana C.
- Shahrokhi, Amene
- Eftekhari, Sanaz
- Venue
- Science
- Published
- 2014-02-07
- Volume
- 343
- Issue
- 6171
- Pages
- 675-679
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2014310721
- Cited by
- 601
- References
- 29
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 30 · 2023: 33 · 2022: 62 · 2021: 46 · 2020: 76 · 2019: 53 · 2018: 59 · 2017: 63 · 2016: 49 · 2015: 58 · 2014: 38
- FWCI
- 38.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Americanae (AECID Library) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-12-RPIB-0001)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- oxytocin, GABAergic inhibition, autism spectrum disorder, delivery, valproic acid, fragile X syndrome, bumetanide, intracellular chloride, glutamatergic activity, gamma oscillations, hippocampal neurons, oxytocin signaling, neuroprotection
- MeSH terms
- Animals, Autistic Disorder, Behavior, Animal, Bumetanide, Chlorides, Disease Models, Animal, Female, gamma-Aminobutyric Acid, Maternal-Fetal Exchange, Oxytocin, Pregnancy, Valproic Acid, Cytoprotection, Parturition, Mice, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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