Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition
Yang, S.; Datta, D.; Krienen, F. M.; Ling, E.; Woo, E.; May, A.; Anderson, G. M.; Galvin, V. C.; Gonzalez-Burgos, G.; Lewis, D. A.; McCarroll, S. A.; Arnsten, A. F.; Wang, M.
Show abstract
Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimers disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and 7-nicotinic receptors (nic-7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.
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