Kynurenic acid signaling expands in human and nonhuman primates and impairs dorsolateral prefrontal cortical cognition that is key to mental illness.

Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, where impairments are correlated with kynurenine inflammatory signaling. Kynurenine synthesis from tryptophan is increased under conditions of inflammation, then further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may contribute to higher cognitive deficits in these disorders. The current study employed several methods to examine the expression of KYNA and its synthetic enzyme, KAT II, in primate dlPFC, and to determine its effects on working memory-related dlPFC neuronal firing and cognitive functioning in aging macaques with naturally-occurring neuroinflammation. We found that KYNA, its synthetic enzyme, KAT II, and the gene encoding KAT II (AADAT), have greatly expanded expression in macaque and human dlPFC in both glia and neurons, with AADAT especially prominent in primate neurons compared to rodent PFC. In macaques, like humans, plasma kynurenine/tryptophan ratios increased with age, consistent with age-related increasing inflammation. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, 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. These data show that KYNA inflammatory signaling expands in primate dlPFC, and that inhibition of kynurenine-KYNA production may provide a powerful therapeutic avenue for treating higher cognitive deficits in neuroinflammatory disorders.