Maria Holtze

Bio: Maria Holtze is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Kynurenic acid & Kynurenine. The author has an hindex of 8, co-authored 8 publications receiving 518 citations.

Increased Levels of Kynurenine and Kynurenic Acid in the CSF of Patients With Schizophrenia

Abstract: Background: The kynurenic acid (KYNA) hypothesis for schizophrenia is partly based on studies showing increased brain levels of KYNA in patients. KYNA is an endogenous metabolite of tryptophan (TRP ...

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls.

Abstract: Funding: This study was financed by grants from the Hallstens Forskningsstiftelse, Swedish Brain Foundation, Svenska Lakaresallskapet, Karolinska Institutet, Torsten och Ragnar Soderbergs stiftelse, Swedish Medical Research Council, Soderstrom-Konigska stiftelsen, the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Copenhagen Hospital Corporation Research Fund, the Danish National Psychiatric Research Foundation, the Danish Agency for Science, Technology and Innovation (Centre for Pharmacogenetics) to T. Werge, the Research Council of Norway (147787, 167153), the Eastern Norway Health Authority (Helse Ost RHF 123/2004), Ulleval University Hospital, and University of Oslo to the TOP study (O.A. Andreassen), the Swedish Research Council (No. 2009-4046 and 2009-7053 [S. Erhardt], K2009-62X-07484-24-3 [G. Engberg], K2007-62X-15077-04-1 [Ingrid Agartz], K2007-62X-15078-04-3 [E.G. Jonsson], K2008-62P-20597-01-3 [E.G. Jonsson], 10909 [M. Schalling]), the Knut and Alice Wallenberg Foundation (L. Terenius) and the HUBIN project. The funding sources had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Competing interests: None declared for M. Holtze and P. Saetre, L. Schwieler, H. Hall, M. Schalling and S. Erhardt. As above for G. Engberg, T. Werge, O.A. Andreassen, L. Terenius, I. Agartz and E.G. Jonsson. T. Werge also declares having received consultancy and lecture fees from Lundbeck A/S. Contributors: M. Holtze coordinated the preparation of the manuscript and wrote the initial draft. P. Saetre performed and drafted the statistical analyses. G. Engberg participated in the study design and supervised the KYNA analyses. L. Schwieler, T. Werge and O.A. Andreassen participated in the study design and performed the KYNA analyses. H. Hall, L. Terenius and I. Agartz participated in the study design and contributed to data collection. E.G. Jonsson participated in the study design, clinical characterization and contributed to data collection. M. Schalling participated in the study design. S. Erhardt participated in the study design, performed the KYNA analyses and helped write the paper. All authors contributed article review and approved the publication of the final manuscript.

Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia.

Abstract: Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.

Neonatal infection with neurotropic influenza A virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1-/- mice.

Abstract: Epidemiological studies suggest that early life infections may contribute to the development of neuropsychiatric disorders later in life. Experimental studies employing infections during neonatal life support this notion by reporting persistent changes in the behaviour of adult animals, including deficits in sensorimotor gating. We have previously described an induction of the kynurenine pathway in neonatal wild-type (WT) mice following a systemic infection with neurotropic influenza A/WSN/33 virus. Here, we use the same model of infection in both WT and Tap1-/- mice (expressing reduced levels of MHC class I) and study long-term effects of the infection on sensorimotor gating, as determined by measuring prepulse inhibition (PPI). Moreover, transcription of genes encoding enzymes in the kynurenine pathway and levels of kynurenic acid (KYNA), in the brain of Tap1-/- mice were investigated. In mice infected on postnatal day (P)3 or P4, the levels of several transcripts in the kynurenine pathway were altered at P7, P13 and P24. Transcripts encoding indoleamine-pyrrole 2,3-dioxygenase (IDO), degrading tryptophan in the first step of the kynurenine pathway were consistently up-regulated at all time-points investigated. The changes in transcript levels were accompanied by a transient elevation of KYNA in the brain of infected mice at P13. At age 5-6 months, neonatally infected Tap1-/-, but not WT, mice exhibited a reduction in PPI. The present data show that a neonatal infection targeting the brain can induce the kynurenine pathway and that such an infection can disrupt sensorimotor gating in adulthood in genetically vulnerable mice.

Induction of the kynurenine pathway by neurotropic influenza A virus infection.

Abstract: Glutamatergic NMDA (N-methyl D-aspartate) receptors play a critical role in brain development and neurotransmission. Kynurenic acid, an end product of tryptophan degradation along the kynurenine pathway, is an endogenous NMDA receptor antagonist. In the present study, the effects of neurotropic influenza A virus infection on the kynurenine pathway were investigated in mouse brain primary cell cultures and in mouse brain after infection on day 3 of postnatal life. Altered levels of transcripts encoding several key enzymes of the kynurenine pathway were observed in infected neuron and glial cell cultures. In vivo, changes in the levels of such transcripts in brain were observed on postnatal days 7 and 13 but not on day 24. On postnatal day 13, infiltrating T lymphocytes and increased levels of kynurenic acid were observed in the brains of the infected animals. Taken together, the present results indicate that central nervous system infections during early life can activate the entire kynurenine pathway. Such activation is likely to result in the generation of several bioactive metabolites, as supported by our finding of a transient increase of kynurenic acid. In light of its antagonistic actions on the NMDA receptor, kynurenic acid can potentially link infections with glutamatergic signaling in the developing brain.

A polygenic burden of rare disruptive mutations in schizophrenia

Abstract: Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Kynurenines in the mammalian brain: when physiology meets pathology

Abstract: The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond

Abstract: L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Abstract: Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 "vitamin" nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.