Dissertation

Kynurenic acid, learning and memory: The glutamate connection

Potter, Michelle C

2008

Overview

Kynurenic acid (KYNA) is an endogenous brain metabolite produced by the kynurenine pathway of tryptophan degradation. It acts as an antagonist of the N-methyl-D-aspartate (NMDA) and alpha 7 nicotinic acetylcholine (a7nACh) receptors, which are involved in glutamatergic and cholinergic neurotransmission and are critical to an efficiently functioning learning and memory system. The hippocampus, a brain area intricately involved in learning and memory, is innervated by both glutamatergic and cholinergic neurons and contains abundant NMDA and a7nACh receptors. This thesis was designed to study if modulation of glutamatergic and cholinergic function by KYNA plays a role in hippocampal-dependent learning and memory. In FVB/N mice, genomic elimination of kynurenine aminotransferase II (KAT II), the main enzyme responsible for KYNA production in the brain, caused a reduction in hippocampal KYNA levels on postnatal day (PND) 21. This was accompanied by increased extracellular hippocampal glutamate levels and improved performance in some well-established learning and memory paradigms. Mutant PND 21 129SvEv mice also displayed reduced KYNA levels, however without similar changes in glutamate levels or performance on the passive avoidance task. At PND 90, when brain KYNA levels in mutant FVB/N mice returned to wild-type levels, cognitive performance of knock-out mice in some, but not all, tasks did not differ from controls. Moreover, acute normalization of KYNA levels in PND 21 KAT II knock-out FVB/N mice did not attenuate the increase in glutamate levels or the improvement in performance on the passive avoidance task. In the rat hippocampus, a bi-directional control of glutamate by KYNA was revealed, with increases in KYNA levels reducing and decreases in KYNA levels raising extracellular glutamate levels. These drug-induced acute changes were subsequently used to evaluate the role of fluctuating KYNA levels in hippocampal-dependent learning and memory tasks. Decreased KYNA levels caused cognitive improvements in Morris water maze performance but not in passive avoidance or object recognition learning. Acutely elevated KYNA levels did not influence performance in the passive avoidance task. Overall, these results indicate that KYNA plays a role in aspects of hippocampal-dependent learning and memory, and this effect appears to be mediated by the glutamatergic system.

• Publisher: ProQuest Dissertations & Theses
• Subject: Neurology / Neurosciences
• ISBN: 0549751785, 9780549751786