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Oxytocin Improves Autistic Behaviors by Positively Shifting GABA Reversal Potential via NKCC1 in Early‐Postnatal‐Stage

Year: 2025

Type: article

Abstract: Accumulating evidence has identified disrupted oxytocin signaling in both autistic patients and animal models of autism. Nevertheless, the specific timing of the impact of oxytocin on social behavior has remained unclear. Using mouse strains from oxytocin‐Cre mice crossed with Cre‐dependent chemogenetic mice, oxytocinergic neuronal activity is selectivity manipulated during the early or late postnatal stages and revealed, for the first time, that the suppression of oxytocinergic neurons in the early rather than late postnatal stage led to the emergence of autistic‐like behaviors. Notably, significantly reduced oxytocin levels are identified specifically during the early postnatal stage in both valproic acid (VPA)‐exposed and Fmr1‐KO mouse brains, along with an impairment of the GABA reversal potential and downregulation of the Na+‐K+‐2Cl− cotransporter (NKCC1) post‐birth. Furthermore, chemogenetic activation of oxytocinergic neurons during the early rather than late postnatal stage effectively restored the aberrant NKCC1 expression and GABAA receptor reversal potential and consequently alleviated autistic‐like behaviors in VPA‐exposed mice. Overall, the results demonstrate that the early postnatal stage may be the unique critical period for oxytocin signaling to regulate GABA reversal potential and promote brain development for prosocial behaviors. These findings suggest an earlier intervention window and strategy for the clinical oxytocin treatment of autism.

Source: Advanced Science

DOI: 10.1002/advs.202415432