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.

Autism spectrum disorder  /  Glufosiante ammonium  /  Offspring  /  Anterior cingulate cortex  /  Astrocyte  /  Pyramidal neurons  /  Inwardly rectifying potassium channel 4.1  /  Desipramine