Early postnatal exposure to bicuculline modulates E/I balance and induces ASD-like behavioral phenotypes in mice.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social interaction deficits and repetitive behaviors. While precise causes of ASD remain elusive, growing evidence highlights that an imbalance in excitatory and inhibitory (E/I) signaling is a pivotal factor in ASD development and modulation. Balanced E/I neurotransmission is critical for circuit formation, synaptic plasticity, and developmental timing. However, key questions persist, including the critical perturbation window, neurological and neurodevelopmental effects, and clinical implications of E/I imbalance. This study investigated early-life modulation of the GABAergic system's impact on E/I balance and ASD-like behaviors in mice. Mice were treated with bicuculline, a GABAA receptor antagonist, from postnatal days 7-11, and behavioral tests were conducted during adolescence. Results revealed deficits in social interaction in both male and female mice and increased repetitive behaviors in bicuculline-treated male mice. Electrophysiological recordings in the mPFC indicated reduced resting membrane potential, heightened neuronal excitability, and a shift in the E/I ratio. In the hippocampus, recordings displayed enhanced LTP and altered synaptic plasticity. DEG analysis of the PFC in bicuculline-treated mice unveiled aberrant gene profiles related to the regulation of synaptic function. Clinical significance and underlying mechanisms of abnormal brain activity, neurodevelopment, and ASD-related behaviors prompted by neonatal bicuculline treatment require further investigation. Nevertheless, these results suggest that GABAergic signaling disruption during the neonatal period might contribute to ASD-related brain pathophysiological changes.