Aberrant Astroglial Kir4.1 Activation in the Anterior Cingulate Cortex Disrupts Neuronal Excitability and Social Deficits

摘要

Objective: The mechanisms by which environmental hazardous factors contribute to autism spectrum disorder(ASD) remain incompletely understood. Prenatal exposure to the widely used herbicide glufosinate ammonium(GLA) has been shown to induce autism-like phenotypes in offspring. This study aims to investigate the underlying neural mechanisms. Methods and Results: The anterior cingulate cortex(ACC) was identified as a particularly vulnerable region in a mouse model of ASD induced by prenatal GLA exposure(PGEO). In PGEO mice, GLA exposure suppressed the action potential firing of pyramidal neurons in the ACC, which was associated with observed social deficits. Furthermore, bioinformatic analysis revealed that autism-related genes are co-expressed with KCNJ10(which encodes the inwardly rectifying potassium channel Kir4.1) in ASD patients. This finding was supported by electrophysiological recordings and desipramine treatment in the ACC of PGEO mice. Computational inference from omics sequencing suggested that Kir4.1 regulates neuronal synapse formation and function via astrocyte-neuron crosstalk. Conclusion: The results indicate that aberrant activation of astroglial Kir4.1 is a key driver of ACC dysfunction and social deficits in offspring mice prenatally exposed to GLA. Pharmacological inhibition of Kir4.1 may therefore represent a promising therapeutic strategy for treating social deficits associated with ASD.

关键词

autism spectrum disorder / glufosiante ammonium / anterior cingulate cortex / astrocyte / inwardly rectifying potassium channel 4.1