Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery

Tyzio, Roman; Cossart, Rosa; Khalilov, Ilgam; Minlebaev, Marat; Hübner, Christian A.; Represa, Alfonso; Ben-Ari, Yehezkel; Khazipov, Roustem

doi:10.1126/science.1133212

Cited by 420 publications

(428 citation statements)

References 30 publications

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“…OT has, however, been found to alter the expression and function of GABA A Rs, albeit via an OTRmediated mechanism (37)(38)(39). Specifically, GABA is the primary excitatory neurotransmitter in immature neurons, but, shortly before parturition, OT, via an OTR-mediated action, triggers a transient reduction in intracellular chloride concentration that switches GABA actions from excitatory to inhibitory (38,39).…”

Section: Discussionmentioning

confidence: 99%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA A receptors (δ-GABA A Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA A Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 μg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats. Using twoelectrode voltage-clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at α4β1δ and α4β3δ recombinant GABA A Rs. Conversely, ethanol had no effect when applied to α4β1 or α4β3 cells, demonstrating the critical presence of the δ subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the δ-selective GABA A R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on δ-GABA A Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA A Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA A Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at δ-GABA A Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.A receptors (δ-GABA A Rs) play a major role in regulating tonic inhibition in the central nervous system (CNS) (1). The δ-GABA A Rs also represent one of the major targets of ethanol in the CNS, particularly at relatively low ethanol concentrations, and mediate some of the rewarding and ataxic effects of ethanol (2-8). For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2). Further, knockdown of δ subunit expression in the medial shell of the nucleus accumbens reduces alcohol intake in rats (6). Finally, overstimulation and subsequent internalization of α4βδ extrasynaptic GABA A Rs after persistent stimulation by ethanol seem to underlie the development of rapid tolerance to the ataxic effects of ethanol (4).The neuropeptide oxytocin (OT) is well-known for its regulatory role in mammalian sociability and various other central and peripheral physiological processes (9). Early preclinical studies suggested that OT can prevent the development of tolerance to the sedative and ataxic effects of ethanol in rodents (10) and also modulate the severity of ethanol withdrawal (11). More recent studies show that OT reduces alcohol intake in rats (12) and reduces the severity of a...

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Section: Discussionmentioning

confidence: 99%

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Bowen

Peters

Absalom

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…During development, however, GABA is excitatory and depolarizing because of high intracellular chloride concentration. Acting in a manner that may alleviate the stress of the birth process and its potential excitatory neurotoxicity, at the time of birth, oxytocin temporarily shifts the chloride concentrations in neurons such that GABA becomes hyperpolarizing and inhibitory (Tyzio et al, 2006;Khazipov et al, 2008). Most recently, Tyzio et al (2014) observed that the transient hyperpolarization induced by oxytocin at birth is absent in two rodent models of autism: the sodium valproate model and a fragile X genetic model.…”

Section: Oxytocin and Vasopressin Impact Brain Developmentmentioning

confidence: 99%

Developmental Perspectives on Oxytocin and Vasopressin

Hammock

2014

Neuropsychopharmacol

167

146

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The related neuropeptides oxytocin and vasopressin are involved in species-typical behavior, including social recognition behavior, maternal behavior, social bonding, communication, and aggression. A wealth of evidence from animal models demonstrates significant modulation of adult social behavior by both of these neuropeptides and their receptors. Over the last decade, there has been a flood of studies in humans also implicating a role for these neuropeptides in human social behavior. Despite popular assumptions that oxytocin is a molecule of social bonding in the infant brain, less mechanistic research emphasis has been placed on the potential role of these neuropeptides in the developmental emergence of the neural substrates of behavior. This review summarizes what is known and assumed about the developmental influence of these neuropeptides and outlines the important unanswered questions and testable hypotheses. There is tremendous translational need to understand the functions of these neuropeptides in mammalian experience-dependent development of the social brain. The activity of oxytocin and vasopressin during development should inform our understanding of individual, sex, and species differences in social behavior later in life.

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“…Moreover the authors established that the maternal hormone OXT is a critical regulator of the GABA polarity shift (Tyzio et al . 2006, 2014). OXT treatment of ASD animals reversed several cellular, physiological and behavioural phenotypes of ASD, and this phenotypic rescue could be blocked with the OXT receptor (OXTR) antagonist SSR126768A.…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

“…OXTR is a G q ‐type GPCR that is abundantly expressed in the hippocampus and neocortex during the perinatal period (Tyzio et al . 2006). Although the role of NKCC1 is firmly established in this phenotype, it will be important to determine the mechanism by which OXTR activation regulates NKCC1 transport.…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery

Cited by 420 publications

References 30 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Developmental Perspectives on Oxytocin and Vasopressin

Regulation of neuronal chloride homeostasis by neuromodulators

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Maternal Oxytocin Triggers a Transient Inhibitory Switch in GABA Signaling in the Fetal Brain During Delivery

Cited by 420 publications

References 30 publications

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

Developmental Perspectives on Oxytocin and Vasopressin

Regulation of neuronal chloride homeostasis by neuromodulators

Contact Info

Product

Resources

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Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats

Oxytocin prevents ethanol actions at δ subunit-containing GABA _A receptors and attenuates ethanol-induced motor impairment in rats