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

: 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.