Abstract
The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.
Highlights
In addition to disturbances in neurotransmitter systems, recent genetic [1], molecular neuropathology [2], and Kynurenine, cytokines, attention, and prefrontal cortex volume in schizophrenia considered to link the immune and neurotransmitter systems.While TRP is commonly thought of as a precursor of the neurotransmitter serotonin, TRP can be degraded to kynurenine (KYN) [10, 11]
Our results support the involvement of the immuneactivated kynurenine pathway (KP) of TRP metabolism in the pathophysiology of a subset of people with schizophrenia having elevated cytokines from five distinct aspects: (1) elevation of KP enzyme mRNAs in human brain, (2) alterations of KP metabolites in human brain, (3) peripheral changes in KP metabolites, (4) peripheral KP measures that link with cognitive deficits, and (5) peripheral KP measures that link with structural human brain volumetric abnormalities
We showed that the mRNA for the KYN-producing enzyme, tryptophan dioxygenase (TDO), and the kynurenic acid (KYNA)-producing enzymes, KATI/II, are increased in patients with schizophrenia who display elevated cytokine levels
Summary
In addition to disturbances in neurotransmitter systems, recent genetic [1], molecular neuropathology [2], and Kynurenine, cytokines, attention, and prefrontal cortex volume in schizophrenia considered to link the immune and neurotransmitter systems.While TRP is commonly thought of as a precursor of the neurotransmitter serotonin, TRP can be degraded to kynurenine (KYN) [10, 11]. KATI and KATII are the biosynthetic enzymes of KYNA in the mammalian brain [6]. KYNA, 3-HK, and QUINA possess neuroactive properties and are known to modulate dopaminergic, nicotinergic, and glutamatergic neurotransmission [14,15,16]. Whereas QUINA is an N-methyl-D-aspartate receptor (NMDAR) agonist that can cause excitotoxic neurodegeneration and 3-HK can cause neuronal apoptosis, KYNA is an NMDAR antagonist that is considered to protect against excitotoxic and apoptotic effects [9, 17]. In schizophrenia, increased KYNA in the brain may lead to excessive NMDAR blockade, which is a known trigger of psychotic symptoms and cognitive deficits (e.g., with NMDAR antagonists phencyclidine and ketamine) [18]
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