Fluctuations in Endogenous Kynurenic Acid Control Hippocampal Glutamate and Memory

Abstract

Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the a7 nicotinic acetylcholine receptor (a7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up-or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 ml) or ESBA (10 mM, 10 ml), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 mM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

“…Kynurenine enzymes are being pursued as clinical targets for neurodegenerative and inflammatory disease, with at least two studies reporting that pharmacological inhibitors improve cognition (Pocivavsek et al ., 2011; Zwilling et al ., 2011). Mechanistic differences between branches of the kynurenine pathway are directly relevant to age‐associated disease in humans, where the dominant pathway branch varies by cell and tissue type (Schwarcz et al ., 2012).…”

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

“…Thus, experimental studies demonstrate that elevated KYNA affects brain glutamatergic/dopaminergic neurotransmission, hereby im plicating activation of the KYN pathway in established mod els of schizophrenia. 18,43,44 Moreover, elevated KYNA induces schizophrenia like behaviour, such as disrupted prepulse in hibition 45 and auditory sensory gating 46 as well as impaired contextual discriminations, 47 spatial working memory 48,49 and attentional set shifting, 50 in rodents. Notably, a specific inhib itor of KYN aminotransferase II, which reduces brain KYNA levels, prevents ketamine induced working memory impair ments and tends to attenuate hallucinatory like behaviours in primates.…”

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

“…We analyzed KYNA and 3HK using HPLC, and they were detected fluorometrically and electrochemically, 13 respec tively (Appendix 1).…”

“…[1][2][3][4] A key mechanism linking the immune system with mood appears to be the activation of the enzyme indoleamine2,3dioxygenase (IDO) and the resultant en hanced conversion of the amino acid tryptophan (TRP) to kynurenine and its neurotoxic downstream metabolites, the free radical generator 3hydroxykynurenine (3HK) and the Nmethyldaspartate (NMDA) receptor agonist quinolinic acid (QUIN). [5][6][7][8][9][10][11] Together with kynurenic acid (KYNA), a neuro inhibitory and neuroprotective metabolite that is formed in a side arm of the kynurenine pathway (KP) of TRP degrada tion and targets a variety of receptors, 12 these mainly glia derived compounds may modulate glutamatergic neurotrans mission, [13][14][15] which is involved in mood disorders. 16 Supporting evidence linking the KP to depression stems from clinical studies showing that a number of patients receiving cytokine therapy experience changes in mood that correlate with re duced levels of TRP and increased levels of kynurenine and QUIN in the circulation.…”