Aberrant astroglial Kir4.1 activation in the anterior cingulate cortex disrupts neuronal excitability and social behavior

Prenatal herbicide exposure is increasingly linked to neurodevelopmental disorders, yet effective pharmacological interventions remain lacking due to unclear pathogenic mechanisms. Here, we demonstrate that prenatal exposure to glufosinate ammonium (GLA), a widely used herbicide, triggers autism-like behaviors, including social deficits and repetitive grooming, in offspring mice. Whole-brain c-Fos mapping, in vivo calcium imaging, and patch-clamp recordings identified hypoactive pyramidal neurons in the anterior cingulate cortex (ACC) as the neural substrate of these behavioral deficits in prenatally GLA-exposed offspring mice. Mechanistically, transcriptomic and multi-omics analyses revealed that astrocyte activation in the ACC drove Kir4.1 potassium channel upregulation, which suppressed CaMKIIα + neuronal excitability via impaired astrocyte-neuron communication. Pharmacological inhibition of astroglial Kir4.1 not only restored neuronal activity but also rescued social deficits in GLA-exposed offspring, underscoring Kir4.1's pivotal role in ACC dysfunction. Our study uncovers a novel astrocyte-neuron axis underlying herbicide-induced neurodevelopmental impairments and identifies Kir4.1 as a therapeutic target for environmental factor-associated autism.