Impaired Kynurenine Pathway Metabolism in The Prefrontal Cortex of Individuals With Schizophrenia
TL;DR: The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.
Abstract: The levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the branched kynurenine pathway (KP) of tryptophan degradation and antagonist of α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors, are elevated in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). Because endogenous KYNA modulates extracellular glutamate and acetylcholine levels in the PFC, these increases may be pathophysiologically significant. Using brain tissue from SZ patients and matched controls, we now measured the activity of several KP enzymes (kynurenine 3-monooxygenase [KMO], kynureninase, 3-hydroxyanthranilic acid dioxygenase [3-HAO], quinolinic acid phosphoribosyltransferase [QPRT], and kynurenine aminotransferase II [KAT II]) in the PFC, ie, Brodmann areas (BA) 9 and 10. Compared with controls, the activities of KMO (in BA 9 and 10) and 3-HAO (in BA 9) were significantly reduced in SZ, though there were no significant differences between patients and controls in kynureninase, QPRT, and KAT II. In the same samples, we also confirmed the increase in the tissue levels of KYNA in SZ. As examined in rats treated chronically with the antipsychotic drug risperidone, the observed biochemical changes were not secondary to medication. A persistent reduction in KMO activity may have a particular bearing on pathology because it may signify a shift of KP metabolism toward enhanced KYNA synthesis. The present results further support the hypothesis that the normalization of cortical KP metabolism may constitute an effective new treatment strategy in SZ.
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TL;DR: The electrophysiological characteristics of ventral tegmental area dopamine neurons and their response to antipsychotic drugs in a KMO knock‐out (K/O) mouse model support the usefulness of KMO K/O mice for studying distinct aspects of the pathophysiology and pharmacological treatment of psychiatric disorders such as schizophrenia.
23 citations
TL;DR: Support for the “KYNA hypothesis” comes from studies in experimental animals in which even relatively moderate increases in brain KYNA result in a spectrum of biochemical and cognitive abnormalities reminiscent of schizophrenia, and interventions leading to a reduction of cerebral KYNA formation may have therapeutic benefits.
Abstract: The levels of the tryptophan metabolite kynurenic acid (KYNA) are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia and may be causally involved in pathophysiology. This view is based on the ability of KYNA to antagonize the function of α7 nicotinic and N-methyl- d -aspartate receptors, both of which are critical to normal brain development and cognitive processes, and are impaired in schizophrenia. Further support of the “KYNA hypothesis” comes from studies in experimental animals in which even relatively moderate increases in brain KYNA result in a spectrum of biochemical and cognitive abnormalities reminiscent of schizophrenia. Interventions leading to a reduction of cerebral KYNA formation may therefore have therapeutic benefits. Most efforts in this regard have focused on inhibiting the astrocytic enzyme kynurenine aminotransferase II, a major route of KYNA neosynthesis in the brain. Promising preclinical results using specific kynurenine aminotransferase II inhibitors have been obtained recently.
22 citations
TL;DR: Experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy and provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
Abstract: Working memory deficits are present in schizophrenia (SZ) but remain insufficiently resolved by medications. Similar cognitive dysfunctions can be produced acutely in animals by elevating brain levels of kynurenic acid (KYNA). KYNA’s effects may reflect interference with the function of both the α7 nicotinic acetylcholine receptor (α7nAChR) and the glycineB site of the NMDA receptor. The aim of the present study was to examine, using pharmacological tools, the respective roles of these two receptor sites on performance in a delayed non-match-to-position working memory (WM) task (DNMTP). DNMTP consisted of 120 trials/session (5, 10, and 15 s delays). Rats received two doses (25 or 100 mg/kg, i.p.) of L-kynurenine (KYN; bioprecursor of KYNA) or L-4-chlorokynurenine (4-Cl-KYN; bioprecursor of the selective glycineB site antagonist 7-Cl-kynurenic acid). Attenuation of KYN- or 4-Cl-KYN-induced deficits was assessed by co-administration of galantamine (GAL, 3 mg/kg) or PAM-2 (1 mg/kg), two positive modulators of α7nAChR function. Reversal of 4-Cl-KYN-induced deficits was examined using D-cycloserine (DCS; 30 mg/kg), a partial agonist at the glycineB site. Both KYN and 4-Cl-KYN administration produced dose-related deficits in DNMTP accuracy that were more severe at the longer delays. In KYN-treated rats, these deficits were reversed to control levels by GAL or PAM-2 but not by DCS. In contrast, DCS eliminated performance deficits in 4-Cl-KYN-treated animals. These experiments reveal that both α7nAChR and NMDAR activity are necessary for normal WM accuracy. They provide substantive new support for the therapeutic potential of positive modulators at these two receptor sites in SZ and other major brain diseases.
22 citations
01 Dec 2020
TL;DR: In this article, postmortem findings of alterations to both cell types in the dorsolateral prefrontal cortex (DLPFC) were found to reflect network activity of excitatory pyramidal neurons and inhibitory GABA neurons and discussed how these findings might inform future biomarker development and use.
Abstract: Certain cognitive deficits in schizophrenia, such as impaired working memory, are thought to reflect alterations in the neural circuitry of the dorsolateral prefrontal cortex (DLPFC). Gamma oscillations in the DLPFC appear to be a neural corollary of working memory function, and the power of these oscillations during working memory tasks is lower in individuals with schizophrenia. Thus, gamma oscillations represent a potentially useful biomarker to index dysfunction in the DLPFC circuitry responsible for working memory in schizophrenia. Postmortem studies, by identifying the cellular basis of DLPFC dysfunction, can help inform the utility of biomarker measures obtained in vivo. Given that gamma oscillations reflect network activity of excitatory pyramidal neurons and inhibitory GABA neurons, we review postmortem findings of alterations to both cell types in the DLPFC and discuss how these findings might inform future biomarker development and use.
22 citations
Cites background from "Impaired Kynurenine Pathway Metabol..."
...Levels of kynurenic acid protein have been reported to be elevated in the DLPFC in schizophrenia [45,46], potentially indicating higher antagonism of the NMDA receptor glycine site....
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TL;DR: The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia.
Abstract: Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i.e., radial glia cells (RGCs), enriched from human cerebral cortex at mid-gestation (16-19 gestational weeks). KYNA treatment significantly decreased RGCs proliferation and survival by antagonizing NMDAR. This alteration resulted in a reduced number of cortical progenitors and neurons while number and activation of astrocytes increased. KYNA treatment reduced differentiation of RGCs into GABAergic neurons, while differentiation into glutamatergic neurons was relatively spared. Furthermore, in mixed cortical cultures KYNA triggered an inflammatory response as evidenced by increased levels of the pro-inflammatory cytokine IL-6. In conclusion, elevated levels of KYNA play a significant role in human RGC fate determination by antagonizing NMDARs and by activating an inflammatory response. The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia.
22 citations
Cites background from "Impaired Kynurenine Pathway Metabol..."
...In rodents, KYNA can cross the placental and fetal blood-brain barriers (Heyes et al., 1990; Scharfman and Goodman, 1998) and induce secretion of various pro-inflammatory cytokines, such as interferon gamma (IFN-γ) and interleukin 6 (IL-6), from fetal astrocytes (Meyer et al., 2011)....
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References
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Journal Article•
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
TL;DR: In this paper, the authors reviewed patterns of frontal-lobe activation associated with a broad range of different cognitive demands, including aspects of perception, response selection, executive control, working memory, episodic memory and problem solving.
2,429 citations
"Impaired Kynurenine Pathway Metabol..." refers result in this paper
...The activity of 3-HAO, which catalyzes the formation of the NMDA receptor agonist quinolinic acid from 3hydroxyanthranilic acid, was found to be reduced in BA 9, ie, the dorsolateral subdivision of the PFC that is preferentially involved in sustaining attention and working memory.(48) A tendency toward lower 3-HAO activity was also observed in BA 10, though the results were not statistically significant....
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TL;DR: Hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.
Abstract: 1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.
886 citations
TL;DR: It is demonstrated that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.
Abstract: The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as an NMDA receptor antagonist. Here, interactions between KYNA and the nicotinic system in the brain were investigated using the patch-clamp technique and HPLC. In the electrophysiological studies, agonists were delivered via a U-shaped tube, and KYNA was applied in admixture with agonists and via the background perfusion. Exposure (≥4 min) of cultured hippocampal neurons to KYNA (≥100 nm) inhibited activation of somatodendritic α7 nAChRs; the IC50 for KYNA was ∼7 μm. The inhibition of α7 nAChRs was noncompetitive with respect to the agonist and voltage independent. The slow onset of this effect could not be accounted for by an intracellular action because KYNA (1 mm) in the pipette solution had no effect on α7 nAChR activity. KYNA also blocked the activity of preterminal/presynaptic α7 nAChRs in hippocampal neurons in cultures and in slices. NMDA receptors were less sensitive than α7 nAChRs to KYNA. The IC50 values for KYNA-induced blockade of NMDA receptors in the absence and presence of glycine (10 μm) were ∼15 and 235 μm, respectively. Prolonged (3 d) exposure of cultured hippocampal neurons to KYNA increased their nicotinic sensitivity, apparently by enhancing α4β2 nAChR expression. Furthermore, as determined by HPLC with fluorescence detection, repeated systemic treatment of rats with nicotine caused a transient reduction followed by an increase in brain KYNA levels. These results demonstrate that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.
764 citations
TL;DR: Kynurenate‐type compounds inhibit glycine binding and are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site, suggesting the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.
Abstract: Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.
623 citations
"Impaired Kynurenine Pathway Metabol..." refers background in this paper
...linked to cognitive phenomena and psychosis, ie, the a7 nicotinic acetylcholine receptor (a7nAChR)(12) and the N-methyl-D-aspartate (NMDA) receptor.(13) By reducing...
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