Nicotinic α7 acetylcholine receptor-mediated currents are not modulated by the tryptophan metabolite kynurenic acid in adult hippocampal interneurons

Abstract

The tryptophan metabolite, kynurenic acid (KYNA), is classically known to be an antagonist of ionotropic glutamate receptors. Within the last decade several reports have been published suggesting that KYNA also blocks nicotinic acetylcholine receptors (nAChRs) containing the α7 subunit (α7*). Most of these reports involve either indirect measurements of KYNA effects on α7 nAChR function, or are reports of KYNA effects in complicated in vivo systems. However, a recent report investigating KYNA interactions with α7 nAChRs failed to detect an interaction using direct measurements of α7 nAChRs function. Further, it showed that a KYNA blockade of α7 nAChR stimulated GABA release (an indirect measure of α7 nAChR function) was not due to KYNA blockade of the α7 nAChRs. The current study measured the direct effects of KYNA on α7-containing nAChRs expressed on interneurons in the hilar and CA1 stratum radiatum regions of the mouse hippocampus and on interneurons in the CA1 region of the rat hippocampus. Here we show that KYNA does not block α7* nACHRs using direct patch-clamp recording of α7 currents in adult brain slices.Kynurenic acid (KYNA) is produced by the metabolism of tryptophan via the kynurenine pathway 1,3 . Classically, KYNA is known for its antagonist actions at ionotropic glutamate receptors, showing the greatest a nity for NMDA-mediated glutamatergic responses 2 . Altered levels of KYNA have been associated with several disease states; increased KYNA levels are seen with Alzheimer's disease, Down's syndrome, and schizophrenia while decreased KYNA levels are associated with end stage Parkinson's and Huntington's disease 3 . Additionally, animal studies indicate that increased brain levels of KYNA are neuroprotective and anti convulsant, while decreased KYNA levels are associated with an increased vulnerability to excitotoxic damage 4 .Another action attributed to KYNA is the antagonism of α7 subunit-containing (α7*) nicotinic acetylcholine receptors (nAChRs). Several reports from Albuquerque and colleagues present data demonstrating that KYNA also blocks the activation of α7* nAChRs 4 . However, a recent report from Mok and colleagues examining the e ects of KYNA on several di erent ligand gated ion channels revealed that KYNA had no e ect on α7* nAChRs 6 . Here we present the results of our investigation of KYNA e ects on α7* nAChRs expressed on interneurons in the hilar and CA1 stratum radiatum (SR) regions of the mouse hippocampus, as well as α7* nAChRs expressed on interneurons the rat CA1 SR. RESULTSKynurenic acid e ects on α7* nAChRs expressed on mouse hilar interneurons e results obtained form choline-induced α7* currents in hilar interneurons are shown in Fig 1. We initially examined the prevalence of α7* currents in hilar interneurons. Out of the 23 neurons studied, 20 displayed choline-induced and methyllycaconitine (MLA) sensitive whole cell currents characteristic of α7* nAChRs. Furthermore, in experiments using α7* null mutant mice, no choline-induced currents were detected (Fig 1a and 1b). Nex...

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

“…coli K1 in a manner similar to the inhibition of α7 nAChR, we next performed comparative analysis of the effects of NMDAR and α7 nAChR inhibitors on bacterial intracellular survivals of HBMEC. The effects of MEM, NMDA (NMDA agonist) and two NMDAR antagonists, kynurenic acid (Kyn) [ 23 ] and dextromethorphan (DM) [ 24 ], were compared using the gentamicin survival assay. As shown in Fig 3 , DM and Kyn ( Fig 3A and 3B ) could not significantly block bacterial intracellular survivals of HBMEC and no dose-dependent effects were observed for these two drugs when compared to that of MEM.…”

“…However, NMDA, a NMDAR agonist, did not show significant stimulating effects at the same concentration. Moreover, the NMDAR antagonists, kynurenic acid [ 23 ] and dextromethorphan [ 24 ] could not significantly block E . coli K1 invasion of HBMEC when compared to the blocking effects mediated MEM at the same dose range.…”