Cortical kynurenine pathway metabolism: a novel target for cognitive enhancement in Schizophrenia

Abstract

The brain concentration of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist at both the glycine coagonist site of the N-methyl-D-aspartic acid receptor (NMDAR) and the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), is elevated in the prefrontal cortex (PFC) of individuals with schizophrenia. This increase may be clinically relevant because hypofunction of both the NMDAR and the alpha7nAChR are implicated in the pathophysiology, and especially in the cognitive deficits associated with the disease. In rat PFC, fluctuations in endogenous KYNA levels bidirectionally modulate extracellular levels of 3 neurotransmitters closely related to cognitive function (glutamate, dopamine, and acetylcholine). Moreover, behavioral studies in rats have demonstrated a causal link between increased cortical KYNA levels and neurocognitive deficits, including impairment in spatial working memory, contextual learning, sensory gating, and prepulse inhibition of the startle reflex. In recent human postmortem studies, impairments in gene expression and activity of kynurenine pathway enzymes were found in cortical areas of individuals with schizophrenia. Additional studies have revealed an interesting association between a sequence variant in the gene of one of these enzymes, kynurenine 3-monooxygenase, and neurocognitive deficits seen in patients. The emerging, remarkable confluence of data from humans and animals suggests an opportunity for developing a rational pharmacology by targeting cortical kynurenine pathway metabolism for cognition enhancement in schizophrenia and beyond.

Figures

Fig. 1.

(A and B): Kynurenine pathway metabolism is initiated by the oxidative ring opening of tryptophan by both indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. In the brain, the pivotal metabolite L-kynurenine is enzymatically converted in microglial cells and astrocytes, respectively. In schizophrenia, a persistent reduction of microglial kynurenine 3-monooxygenase activity, possibly accompanied by increased L-kynurenine influx from the circulation, results in increased kynurenic acid formation in astrocytes. See text for further details.