Astroglial disinhibition of cortical circuits disrupts cognition via kynurenic acid in mice

Abstract

Abstract Astrocytes play critical roles in neural circuit function, but how they contribute to cognitive impairment remains poorly understood. Here, we identify astrocyte-derived kynurenic acid (KYNA), a neuroactive metabolite known to modulate multiple neurotransmitter receptor systems, including the N-methyl-D-aspartate receptor (NMDA), as a mediator of cognitive dysfunction in the context of aberrant astrocyte activity. Using chemogenetic stimulation, pharmacological rescue, and astrocyte-specific knockdown of kynurenine aminotransferase II (KAT II) in mice, we show that elevated KYNA suppresses parvalbumin-positive interneuron activity in the prefrontal cortex, leading to disinhibition of pyramidal neurons and impairments in cognitive functions linked to cortical activity, including episodic-like and working memory as well as sensorimotor gating. These findings define an astrocyte-KYNA-interneuron axis that controls cortical excitability and cognition, linking glial metabolism to circuit imbalance and cognitive dysfunction with potential relevance to psychiatric and neurological disorders.