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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30 Aug 2021
TL;DR: In this paper, the authors investigated spatial working memory in mice with elevated levels of kynurenine 3-monooxygenase (KMO), as well as longterm potentiation (LTP) of field excitatory postsynaptic potentials (fEPSPs) in hippocampal brain slices from these mice.
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.
4 citations
TL;DR: The crystal structure of the Pyrococcus horikoshii KAT in complex with pyridoxamine phosphates (PMP), KYN, and KYA shows that an amino group of KYN was transaminated to PLP, which forms a Schiff's base with the LYS-269 of the KYN.
4 citations
Cites background from "Impaired Kynurenine Pathway Metabol..."
...Recently, Schwarcz et al. reported that the levels of KYA are elevated in the prefrontal cortex of individuals with schizophrenia (Sathyasaikumar et al., 2010)....
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...reported that the levels of KYA are elevated in the prefrontal cortex of individuals with schizophrenia (Sathyasaikumar et al., 2010)....
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01 Jan 2021
TL;DR: Evidence for a key role of inflammation in schizophrenia is presented and the immune system may be a potential target for novel treatments for schizophrenia, supported by several findings.
Abstract: This chapter presents evidence for a key role of inflammation in schizophrenia. In animal models, an immune response during the pre- or perinatal phase has been shown to affect lifelong immune function. Furthermore, levels of cytokines and other pro-inflammatory compounds are higher in people with schizophrenia than in healthy controls. Evidence from epidemiological and clinical studies shows that certain infections increase the risk for psychosis, in particular schizophrenia. The so-called vulnerability-stress-inflammation model has been proposed to explain how inflammation is involved in schizophrenia. According to this model, schizophrenia is related to risk genes for inflammation, alterations in the immune system, and exposure to environmental stress factors. Stress is known to increase cytokine levels and may play a role in a chronic proinflammatory state. The proposed involvement of low-level neuroinflammation in schizophrenia is supported by several findings: altered neurotransmission is a typical feature of both neuroinflammation and schizophrenia; patients with schizophrenia have a loss of volume in central nervous system structures and activated microglia; anti-inflammatory drugs have positive effects in schizophrenia; and antipsychotics have anti-inflammatory and immunomodulatory effects. Together, these findings indicate that the immune system may be a potential target for novel treatments for schizophrenia.
4 citations
Dissertation•
05 Sep 2014
TL;DR: The findings suggest that the GRK3 mouse is a novel genetic animal model of schizophrenia that may prove useful in exploring the actions of the emerging immunomodulatory drugs in psychotic disorders and imply that contemporary glia research can provide a rewarding foundation for investigations into pathology of psychiatric disorders.
Abstract: Neuroinflammation has been implicated in several psychiatric conditions. Based on experimental studies, the glia-derived tryptophan metabolite kynurenic acid (KYNA) may be especially relevant for positive psychotic symptoms and impaired executive functioning. The first two studies (I and II) of this thesis translate these experimental findings to bipolar disorder patients. Rooted in a genome-wide association study against cerebrospinal fluid (CSF) concentrations of KYNA, we used a multi-pronged approach and linked the identified genetic risk marker not only with other CSF biomarkers in bipolar patients, but also with specific symptoms such as delusions, hallucinations, and impaired executive functioning. We conducted cell studies, postmortem analyses, and clinical association studies that together suggested a sorting nexin 7 driven activation of caspase-8/IL-1ß as a mechanism underlying increased CSF concentration of KYNA in psychotic bipolar patients. Caspase-1 is activated by the purinergic ionotropic receptor P2X7R. This receptor is suggested to be internalized by a G-protein coupled receptor kinase 3 (GRK-3)-dependent mechanism. Decreased protein levels of GRK-3 have been observed in postmortem studies of schizophrenia and psychotic bipolar patients. In study III, we used a mouse with a targeted deletion for GRK3. These mice displayed impaired P2X7R internalization, increased brain levels of IL-1ß, increased immunoreactivity for the astrocytic marker glial fibrillary acidic protein (GFAP), a more pronounced accumulation of hippocampal KYNA, as well as an accentuated dopaminergic response to amphetamine. In behavior models, these animals displayed disrupted pre-pulse inhibition, as well as impaired contextual fear conditioning with spared cue-specific fear conditioning. Taken together, these findings suggest that the GRK3 mouse is a novel genetic animal model of schizophrenia that may prove useful in exploring the actions of the emerging immunomodulatory drugs in psychotic disorders. Study IV was a validation study aiming at defining an algorithm that identifies bipolar disorder patients in Swedish national registries as accurate as possible, a pre-requisite for study V. In the last study V of this thesis, we studied the association between psychotic disorders and rheumatoid arthritis (RA). We found that the previously reported inverse association is likely to have been confounded by underreporting and/or underdiagnosis of RA. However, an inverse association between schizophrenia and seronegative RA may be real, tentatively due to shared genetic underpinnings involving glia functioning. In conclusion, this thesis suggests an important role of glial mechanisms in the pathophysiology of the two main psychiatric disorders, schizophrenia and bipolar disorder. Our results add to growing evidence that cytokine and kynurenine metabolite signaling is tied to psychotic and cognitive symptoms. These findings open up for novel drug targets and imply that contemporary glia research can provide a rewarding foundation for investigations into pathology of psychiatric disorders. LIST OF PUBLICATIONS I. Sara K Olsson*, CARL SELLGREN*, Göran Engberg, Mikael Landén, Sophie Erhardt. Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. Bipolar Disorders. 2012; 14: 719-726. *These authors contributed equally to this work. II. CARL SELLGREN*, Magdalena E. Kegel*, Sarah E. Bergen, Carl Johan Ekman, Sara Olsson, Markus Larsson, Marquis P. Vawter, Martin Schalling, Lena Backlund, Patrick F. Sullivan, Pamela Sklar, Jordan W. Smoller, Patrik K.E. Magnusson, Christina M. Hultman, Lilian WaltherJallow, Camilla I. Svensson, Paul Lichtenstein, Göran Engberg, Sophie Erhardt, Mikael Landén. An inflammatory pathway linked to psychosis in bipolar disorder. Submitted. * These authors contributed equally to this work. III. CARL SELLGREN*, Markus Larsson*, Funda Orhan, Magdalena E Kegel, Ida Nilsson, Susan B Powell, S Caldwell, M Kamenski, Sarah E Bergen, Lilly Schwieler, Camilla I Svensson, Paul Lichtenstein, Martin Schalling, Mikael Landén, Göran Engberg, Sophie Erhardt. Targeting of GRK-3 identifies a molecular pathway leading to glial activation in psychotic disorders. * These authors contributed equally to this work. IV. CARL SELLGREN, Mikael Landén, Paul Lichtenstein, Christina M Hultman, Niklas Långström. Validity of bipolar disorder hospital discharge diagnoses: file review and multiple register linkage in Sweden. Acta Psychiatrica Scandinavica. 2011; 124: 447-453. V. CARL SELLGREN, Thomas Frisell, Paul Lichtenstein, Mikael Landén, Johan Askling. The Association Between Schizophrenia and Rheumatoid Arthritis: A Nationwide Population-Based Swedish Study on Intraindividual and Familial Risks. Schizophrenia Bulletin. 2014; Apr 8. CONTENTS
3 citations
Cites background from "Impaired Kynurenine Pathway Metabol..."
...20 bipolar disorder (Holtze et al., 2011; Lavebratt et al., 2014; Sathyasaikumar et al., 2011), suggesting a scenario in which IL-1β driven KYNA production can be further enhanced....
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...…(Stone, 1993), as well as the alpha-7-nicotinic acetylcholine receptor (competitively) (α7nAChR) (Hilmas et al., 2001), and studies of postmortem frontal cortex obtained from individuals with schizophrenia have revealed increased levels of KYNA (Sathyasaikumar et al., 2011; Schwarcz et al., 2001)....
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...Increased levels of KYN and KYNA have indeed also been observed in postmortem prefrontal cortex of schizophrenia patients, while 3-HK levels were unaltered (Sathyasaikumar et al., 2011; Schwarcz et al., 2001)....
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...In addition, decreased KMO activity has been implicated in both schizophrenia and psychotic 20 bipolar disorder (Holtze et al., 2011; Lavebratt et al., 2014; Sathyasaikumar et al., 2011), suggesting a scenario in which IL-1β driven KYNA production can be further enhanced....
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..., 2001), and studies of postmortem frontal cortex obtained from individuals with schizophrenia have revealed increased levels of KYNA (Sathyasaikumar et al., 2011; Schwarcz et al., 2001)....
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Dissertation•
26 Mar 2018
TL;DR: The results of this thesis strengthen the idea that immune dysfunctions affect tryptophan metabolism as well as GABAergic and dopaminergic neurotransmission in early schizophrenia.
Abstract: Growing evidence suggests a role of low-grade inflammation in the pathophysiology of schizophrenia, giving rise to a dysregulation in neurons containing dopamine and glutamate as well as γ-aminobutyric acid (GABA). In this thesis, a role of peripheral and brain-immune signaling molecules, as well as brain neurotransmitters, was investigated in a wellcharacterized cohort of first-episode psychosis (FEP) patients. Using human monocyte cultures, toll-like receptor (TLR) activation was analyzed to study the production of metabolites along the kynurenine pathway. We found that stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8, and TLR-9 induced the pathway, whereas activation of TLR-1/2, TLR-5, and TLR-2/6 did not. Interestingly, only activation of TLR-3 induced the production kynurenic acid (KYNA), a neuroactive metabolite implicated in psychotic disorders. In FEP patients, the number of blood monocytes, as well as plasma concentrations of the chemokines chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1/CCL2), was elevated compared to healthy controls. In addition, FEP patients displayed elevated plasma levels of interleukin (IL)-18 and the levels associated with the cognitive impairments observed in FEP patients, i.e., reduced speed of processing. Moreover, FEP patients displayed lower GABA levels in the cerebrospinal fluid (CSF) compared to healthy controls. CSF GABA concentrations were negatively correlated with scores of cognitive performance and severity of symptoms. Preliminary data also showed higher CSF dopamine concentrations in FEP patients compared to healthy controls. The results of this thesis strengthen the idea that immune dysfunctions affect tryptophan metabolism as well as GABAergic and dopaminergic neurotransmission in early schizophrenia. Also, the data may provide new opportunities to identify biological markers, urgently needed for the diagnosis of the disorder. LIST OF SCIENTIFIC PAPERS I. Orhan F, Bhat M, Sandberg K, Ståhl S, Piehl F, Karolinska Schizophrenia Project (KaSP) consortium, Svenssson C, Erhardt S, Schwieler L. Tryptophan metabolism along the kynurenine pathway. Downstream of toll-like receptor stimulation in peripheral monocytes. Scandinavian Journal of Immunology, 2016. II. Funda Orhan, Lilly Schwieler, Helena Fatouros-Bergman, Anna Malmqvist, Simon Cervenka, Karin Collste, Lena Flyckt, Lars Farde, Carl M Sellgren, Karolinska Schizophrenia Project (KaSP) consortium, Fredrik Piehl, Göran Engberg, Sophie Erhardt. Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis. [Manuscript] III. Orhan F, Fatouros-Bergman H, Schwieler L, Cervenka S, Sellgren CM, Karolinska Schizophrenia Project (KaSP), G Engberg, S Erhardt. Firstepisode psychosis patients display increased plasma IL-18 that correlates with cognitive dysfunction. Schizophrenia Research, 2017. IV. Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, Karolinska Schizophrenia Project (KaSP) Consortium, Cervenka S, Collste K, Victorsson P, Sellgren CM, L Flyckt, S Erhardt, G Engberg. CSF GABA is reduced in first episode psychosis and associates to symptoms severity. Molecular Psychiatry, 2017.
3 citations
Cites background or result from "Impaired Kynurenine Pathway Metabol..."
...Thus, elevated TDO2 mRNA and protein levels (C. L. Miller et al., 2004; C. L. Miller et al., 2006) as well as decreased KMO activity (Sathyasaikumar et al., 2011) have been found in patients....
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..., 2006) as well as decreased KMO activity (Sathyasaikumar et al., 2011) have been found in patients....
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..., 2005) the postmortem brain (Sathyasaikumar et al., 2011; Schwarcz et al., 2001b) of patients with schizophrenia....
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...The hypothesis is supported by studies showing higher levels of KYNA and its immediate precursor kynurenine in both CSF (Erhardt et al., 2001; Linderholm et al., 2012; Nilsson et al., 2005) the postmortem brain (Sathyasaikumar et al., 2011; Schwarcz et al., 2001b) of patients with schizophrenia....
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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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