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.

Regulation of neuronal chloride homeostasis by neuromodulators

“…In line with this hypothesis Tyzio et al . (2014) and He et al . (2014) demonstrated that in different mouse models of ASD, neuronal Cl − homeostasis and GABA polarity are fundamentally altered, such that neurons retain high [Cl − ] i and depolarizing E GABA .…”

“…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.…”

“…2014; Hübner, 2014; Tyzio et al . 2014). Therefore it is of paramount importance to understand the critical regulators of KCC2 function in depth, with the goal of discovering how KCC2 function can be maintained or restored in the face of pathophysiological perturbations.…”

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader–Willi Syndrome

“…by guest on April 20, 2019 www.aappublications.org/news Downloaded from the deleterious effects of enhanced activity of GABA signaling, 27 in addition to the current evidence of changes in brain connectivity after OXT administration in infants <6 months old, suggest a continuum in the role of OXT from birth to early postnatal life.…”

Chloride cotransporter NKCC1 inhibitor bumetanide protects against white matter injury in a rodent model of periventricular leukomalacia

“…Currently, bumetanide is under study in a phase I/II clinical trial as a single add-on therapy to existing phenobarbital treatment for neonatal seizures in infants 33-44 wks of age at dosages of 0.1-0.3 mg/kg (clinicaltrials.gov, NCT00830531). Interestingly, autistic behaviors, one of the developmental outcomes associated with PVL in survivors of preterm birth, have been shown to decrease in a small cohort of human subjects following bumetanide treatment (16,17); bumetanide treatment has also been shown to restore abberant behavior and brain oscillations in animal models of autism when given prenatally (18).…”