Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats

Abstract

The tryptophan metabolite kynurenic acid can block glutamate at ionotropic receptors, but recent evidence suggests a more potent antagonistic action at alpha7 nicotinic receptors for acetylcholine on cultured neurons. The present study examines activity of kynurenic acid at those nicotinic receptors, which mediate cholinergic neurotransmission onto interneurons in the rat hippocampus. Intracellular recordings were made from pyramidal cells and interneurons in the presence of atropine, bicuculline methobromide, (3-aminopropyl)(diethoxymethyl)-phosphinic acid [CGP35348, to block gamma-aminobutyric acid (GABA)(B) receptors] and 3-tropanyl-3,5-dichlorobenzoate (MDL 72222, to block 5-HT3 receptors). In the added presence of glutamate antagonists 2-amino-5-phosphono-pentanoic acid and 6-cyano-7-nitroquinoxaline-2,3-dione, interneurons exhibited a residual excitatory postsynaptic potential (EPSP) that could be blocked by the nicotinic alpha7 receptor blocker methyl-lycaconitine, but not by dihydro-beta-erythroidine which blocks alpha4beta2 receptors. Kynurenic acid reduced the amplitude of these EPSPs with an EC50 of 136 microM. The amplitudes of nicotinic spontaneous miniature EPSPs were also reduced by methyl-lycaconitine and kynurenic acid. The results show that kynurenic acid is more potent in blocking nicotinic EPSPs compared with the full, glutamate-mediated EPSPs, but it was substantially less potent than has been reported in cultures, possibly because of differences in the accessibility of synaptic and extrasynaptic receptors. It is suggested that blockade of nicotinic synaptic transmission may be relevant to the actions of kynurenic acid in the hippocampus, but that in the intact brain this activity is likely to be comparable in importance to the blockade of glutamate-mediated transmission.

Biochemical and Structural Properties of Mouse Kynurenine Aminotransferase III

“…KYNA is also an antagonist of the ␣7-nicotinic acetylcholine receptor (1,27,43,53). KYNA was recently identified as an endogenous ligand for an orphan G-protein-coupled receptor (GPR35) that is predominantly expressed in immune cells (57).…”

Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects

“…38 Furthermore, as discussed by Heyes and colleagues, 39 the concentration of quinolinic acid in the human brain and CSF is 1-3 orders of magnitude above control levels in inflammatory disorders that are associated with neurologic deficits, suggesting that a putative decline from normal quinolinic acid levels after ATD is unlikely to have any important functional significance. Kynurenic acid also has an antagonistic action at nicotinic receptors, 40 and reducing rat brain kynurenic acid with an inhibitor of kynurenine aminotransferase, the enzyme that converts kynurenine to kynurenic acid, improves performance in the Morris water maze, suggesting that kynurenic acid is normally present in physiologically relevant concentrations in the brain. However, ATD does not lower human plasma kynurenic acid levels.…”

Age Dependency of Inhibition of α7 Nicotinic Receptors and Tonically Active N-Methyl-d-aspartate Receptors by Endogenously Produced Kynurenic Acid in the Brain

“…However, studies from numerous laboratories have demonstrated that KYNA also inhibits ␣7 nicotinic acetylcholine receptors (nAChRs) (Hilmas et al, 2001;Alkondon et al, 2004;Lopes et al, 2007;Stone, 2007;Arnaiz-Cot et al, 2008). Identifying the molecular targets that are accessible to the actions of endogenously produced KYNA in the brain is key to understanding the pathophysiology of a number of catastrophic neurological disorders in which brain levels of KYNA are altered, including Alzheimer's disease, schizophrenia, and Huntington's disease (Beal et al, 1992;Baran et al, 1999;Erhardt et al, 2007).…”