Overactivation of prefrontal astrocytes impairs cognition through the metabolic pathway of central kynurenines

ABSTRACT Astrocyte dysfunctions have long been implicated in psychiatric and cognitive disorders, yet the precise mechanisms underlying this association remain elusive. Here, we show that chemogenetic activation of prefrontal astrocytes in mice impairs short-term memory and sensorimotor gating and attenuates the activation of parvalbumin (PV) interneurons in the prefrontal cortex. These alterations are accompanied by increases in prefrontal levels of kynurenic acid (KYNA), a key metabolite of the kynurenine (KYN) pathway, known to be produced by astrocytes, which serves as an endogenous antagonist of NMDA receptors. Pharmacological inhibition of kynurenine aminotransferase II, the key enzyme mediating the transamination of KYN to KYNA, reinstates the astrocyte-mediated impairments in short-term memory and sensorimotor gating, and normalizes the deficits in prefrontal PV interneuron activation. Our study identifies a mechanistic link between overactivation of prefrontal astrocytes, increased production of KYNA, and cognitive as well as cellular dysfunctions involved in major psychiatric disorders and beyond.