The impact of kynurenine pathway activation in glia on neuronal integrity

Abstract

The kynurenine pathway, which is activated in times of stress and infection has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders. Alterations in neuronal integrity, including neuronal cell death, neuritic atrophy and synapse loss are neurodegenerative features often implicated in the pathophysiology of these disorders. Activation of this tryptophan metabolising pathway results in the production of neuroactive metabolites which have the potential to interfere with normal neuronal functioning, and may contribute to altered neuronal transmission and the emergence of symptoms of these brain disorders. The pathway is compartmentalised within different brain cells as a consequence of preferential expression of specific enzymes. For the most part, microglia contain the neurotoxic arm of this pathway on the basis that they produce the oxidative metabolites 3-hydroxykynurenine, and 3 hydroxyanthranillic acid, alongside the NMDA receptor agonist and oxidative metabolite, quinolinic acid. In contrast, astrocytes are responsible for driving the neuroprotective arm of the pathway with the production of the NMDA receptor antagonist, kynurenic acid.