Role of kynurenic acid in higher cognitive deficits: Mechanism and treatment strategies

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The proposed research will examine whether increased kynurenine inflammatory signaling with advancing age impairs higher cortical function through blockade of NMDAR and α7-nAChR, producing cognitive deficits that can be reversed by agents that inhibit kynurenine metabolism. Inflammation induces the conversion of tryptophan to kynurenine, a process that increases with age, and becomes especially prominent in Alzheimer’s Disease (AD), and with infection (e.g. from COVID19). Importantly, kynurenine is further metabolized to kynurenic acid (KYNA), which blocks NMDAR and likely α7-nAChR. Our research has shown that the working memory-related firing of “Delay cells” in primate dorsolateral prefrontal cortex (dlPFC) is heavily dependent on NMDAR neurotransmission with permissive α7-nAChR actions. As KYNA blocks both of these receptors, the increased production of KYNA in the aging brain may be particularly detrimental to dlPFC neuronal firing, and may contribute to the reduced dlPFC neuronal firing and working memory deficits observed in aged monkeys. The proposed research will perform the first examination of KYNA actions on primate dlPFC neuronal firing during working memory in young vs. aged rhesus monkeys, and will test for its interactions with NMDAR and α7-nAChR. We will also examine strategies to restore neuronal firing and working memory performance in aged monkeys by reducing KYNA production, coupled with enhanced cholinergic actions to optimize dlPFC neuronal physiology. These data may provide strategies to protect higher cortical circuits in cognitive disorders with high levels of KYNA production such as AD. Aim 1 will examine how local iontophoresis of exogenously applied KYNA (Aim 1A), or agents that alter the endogenous generation of KYNA (Aim 1B), influences Delay cell firing in young and aged monkeys. Preliminary data indicate that KYNA greatly reduces working memory- related neuronal firing, and that inhibition of KYNA synthesis can boost delay-related firing in aged monkey neurons. Aim 2 will test for KYNA actions at the glycine site on the NMDAR (Aim 2A), and at α7-nAChR (Aim 2B) in dlPFC, testing the hypothesis that KYNA blockade of these receptors markedly reduces Delay cell firing. Preliminary data are consistent with KYNA having both NMDAR and α7-nAChR blocking properties. Aim 3 will examine strategies to optimally restore dlPFC Delay cell firing (Aim 3A) and working memory performance (Aim 3B) in aged monkeys by combining agents that inhibit KYNA production with galantamine, a cholinesterase inhibitor and α7-nAChR positive allosteric modulator that is already approved for the treatment of AD. Given that dlPFC Delay cells require both NMDAR and α7-nAChR stimulation to sustain firing, we hypothesize that this combination may optimize dlPFC physiology and working memory performance in aged monkeys. The use of oral administration of compounds in Aim 3B may identify dosing regimens that can facilitate translation to human use, boosting higher cognitive abilities in patients with AD or other inflammatory disorders, e.g. “long-COVID”, associated with dlPFC cognitive deficits and high levels of kynurenine.