Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 35 (8), 1734-42

Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior

Affiliations

Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior

Michelle C Potter et al. Neuropsychopharmacology.

Abstract

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the alpha 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (-71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro. These functional changes were accompanied by reduced extracellular KYNA (-66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo. Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.

Figures

Figure 1
Figure 1
KYNA and glutamate in the hippocampus of KAT II knock-out (KO) mice and age-matched wild-type (WT) animals. (a) Tissue levels of KYNA in KAT II KO (N=16) and WT (N=17) mice. Data are the mean±SEM. *p<0.05 vs WT controls; basal extracellular KYNA (b) and glutamate (c) levels, respectively, in KAT II KO mice and WT mice, measured by in vivo microdialysis. Data are the mean±SEM (N=6 per group). *p<0.05 vs WT controls.
Figure 2
Figure 2
Improved performance of KAT II knock-out (KO) mice in an object exploration and recognition paradigm. (a) Locomotor activity (open field) and (b) object exploration (habituation to environment). Mutant mice habituated at a faster rate; (c) response to spatial change (object displacement). Compared with the baseline established in S4, KAT II KO animals spent more time than WT mice exploring the displaced object (DO) in sessions S5 and S6. Negative values reflect continued habituation in 21-day-old wild-type (WT) mice. Data are the mean±SEM of 16 animals per group. *p<0.05 vs WT controls.
Figure 3
Figure 3
Improved performance of KAT II knock-out (KO) mice in passive avoidance (contextual memory) and spatial discrimination (T-maze) tests. (a) Performance of KAT II KO and wild-type (WT) mice in a passive avoidance paradigm. Latency is defined as the difference between the times taken to enter the dark compartment on the two test days. Data are the mean±SEM of 16 KAT II KO and 17 WT mice. *p<0.05 vs WT controls. (b) Number of correct choices (to locate a sucrose reward from a goal box) as a function of training days in a T-maze. Mice were 21 days old on the first day of the trial. Five correct choices represent chance (dashed line). (c) Latency to choose either the reinforced or the non-reinforced arm. Data in (b, c) are the mean±SEM of 19 KAT II KO and 15 WT mice. *p<0.05 vs WT controls.
Figure 4
Figure 4
Enhanced LTP amplitude in hippocampal slices obtained from 21–28-day-old KAT II knock-out (KO) and age-matched wild-type (WT) mice. (a) All values are expressed relative to the baseline, ie the average of the responses during a 10 min period before LTP induction. Each point represents the average of the responses recorded in 60 s. Application of the NMDAR antagonist AP-5 (50 μM) blocked LTP in slices from either genotype. Data are the mean±SEM (12 slices per group). *p<0.05 vs WT controls. No significant genotypic differences were observed in NMDAR properties (resting membrane potential, firing pattern, and action potential amplitude) (b, c) or the AMPAR/NMDAR ratio (using average peak EPSCs at +40 mV) (d, e).

Similar articles

See all similar articles

Cited by 81 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback