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

Sophie Imbeault,Holger Wigström,Max Gubert Olivé,Kent Jardemark,Göran Engberg,Oscar Jungholm,Sophie Erhardt

doi:10.1177/11786469211041368

Sophie Imbeault, Holger Wigström + Show 5 more

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https://doi.org/10.1177/11786469211041368

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Abstract

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.

Highlights

Tryptophan degradation along the kynurenine pathway (Figure 1) has become fundamental in contemporary thoughts about the pathophysiology of psychiatric illnesses
We found that kynurenine 3-monooxygenase (KMO)−/− mice show deficits in spatial working memory and that hippocampal excitability and LTP in these mice are related to kynurenic acid (KYNA) synthesis
We tested spatial working memory, which depends on the hippocampus,[33] using the rewarded alternations paradigm in the T-maze

Summary

Introduction

Tryptophan degradation along the kynurenine pathway (Figure 1) has become fundamental in contemporary thoughts about the pathophysiology of psychiatric illnesses. There are a number of clinical studies supporting a role for KYNA in cognition and elevated brain KYNA is shown to underlie impairment of cognitive functions in bipolar disorder,[4] Herpes Simplex encephalitis,[27] and cerebral malaria.[28]

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