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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月8日

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  • Viktor Beilmann,
  • Johanna Furrer,
  • Sina M. Schalbetter,
  • Ron Schaer,
  • Edoardo Tiziani,
  • Kim D. Ferrari,
  • Felisa Herrero,
  • Celine Heeb,
  • Alexandra von Faber-Castell,
  • Jacqueline Condrau,
  • Ulrike Weber-Stadlbauer,
  • Matthias T. Wyss,
  • Aiman S. Saab,
  • Sarah Beggiato,
  • Urs Meyer,
  • Bruno Weber,
  • Tina Notter

摘要

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.