Blockade of KAT II Facilitates LTP in Kynurenine 3-Monooxygenase Depleted Mice

• Published in: International journal of tryptophan research Vol. 14; pp. 117864692110413 - 11786469211041368
• Main Authors: Imbeault, Sophie, Gubert Olivé, Max, Jungholm, Oscar, Erhardt, Sophie, Wigström, Holger, Engberg, Göran, Jardemark, Kent
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 2021; Sage Publications Ltd
• Subjects: acid; activation; Animal memory; brain; cerebrospinal-fluid; d-aspartate receptors; electrophysiology; elevated levels; glycine; hippocampal plasticity; hippocampus; Kynurenine; long-term potentiation; Medicin och hälsovetenskap; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Original Research; pathway-metabolism; site; spatial memory; spatial working-memory; Kynurenine; hippocampus; electrophysiology; spatial memory; long-term potentiation
• ISSN: 1178-6469; 1178-6469
• DOI: 10.1177/11786469211041368

Excess of brain kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is known to elicit cognitive dysfunction. In the present study, we investigated spatial working memory in mice with elevated levels of KYNA, induced by targeted deletion of kynurenine 3-monooxygenase (KMO), as well as long-term potentiation (LTP) of field excitatory postsynaptic potentials (fEPSPs) in hippocampal brain slices from these mice. The KMO knock-out (KMO−/−) mice performed more poorly in the spatial working memory task as compared to their wild-type (WT) counterparts, as reflected by fewer correct choices in a T-maze. Both fEPSPs, or LTP, did not significantly differ between the 2 mouse strains. However, administration of PF-04859989, a kynurenine aminotransferase (KAT) II inhibitor, limiting the production of KYNA, facilitated fEPSP and enhanced LTP to a greater extent in hippocampal slices from KMO−/− mice compared to WT mice. The results of the present study point to an essential role for KYNA in modulating LTP in the hippocampus of KMO−/− mice which may account for their dysfunctional spatial working memory.