The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The ...kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia.
This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’.
Abstract Background Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway—which is implicated as dysfunctional in various psychiatric ...disorders—toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N -methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. Methods In the present study, we investigated adaptive—and possibly regulatory—changes in mice with a targeted deletion of Kmo ( Kmo –/– ) and characterized the kynurenine 3-monooxygenase–deficient mice using six behavioral assays relevant for the study of schizophrenia. Results Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo –/– mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo –/– mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo –/– mice showed potentiated horizontal activity in the open field paradigm. Conclusions Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.
The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are ...reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3
mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3
mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders.
The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites suggested to be involved in a wide variety of diseases and disorders, however, technical challenges in ...reliably detecting these metabolites hampers cross-comparisons. The main objective of this study was to develop an accurate, robust and precise bioanalytical method for simultaneous quantification of ten plasma kynurenine metabolites. As a secondary aim, we applied this method on blood samples taken from healthy subjects conducting 1 session of sprint interval exercise (SIE). It is well accepted that physical exercise is associated with health benefits and reduces risks of psychiatric illness, diabetes, cancer and cardiovascular disease, but also influences the peripheral and central concentrations of kynurenines. In line with this, we found that in healthy old adults (n = 10; mean age 64 years), levels of kynurenine increased 1 hour (P = .03) after SIE, while kynurenic acid (KYNA) concentrations were elevated after 24 hours (P = .02). In contrast, no significant changes after exercise were seen in young adults (n = 10; mean age 24 years). In conclusion, the described method performs well in reliably detecting all the analyzed metabolites in plasma samples. Furthermore, we also detected an age-dependent effect on the degree by which a single intense training session affects kynurenine metabolite levels.
NF-E2 related factor (Nrf2) controls a pleiotropic cellular defense, where multiple antioxidant/detoxification pathways are
up-regulated in unison. Although small molecule inducers of Nrf2 activity ...have been reported to protect neurons in vitro , whether similar pathways can be accessed in vivo is not known. We have investigated whether in vivo toxicity of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) can be attenuated by constitutive and inducible
Nrf2 activity. The absence of Nrf2 function in Nrf2 â/â mice resulted in 3-NP hypersensitivity that became apparent with time and increasing dose, causing motor deficits and striatal
lesions on a more rapid time scale than identically treated Nrf2 +/+ and Nrf2 +/â controls. Striatal succinate dehydrogenase activity, the target of 3-NP, was inhibited to the same extent in all genotypes
by a single acute dose of 3-NP, suggesting that brain concentrations of 3-NP were similar. Dietary supplementation with the
Nrf2 inducer tert -butylhydroquinone attenuated 3-NP toxicity in Nrf2 +/â mice, but not Nrf2 â/â , confirming the Nrf2-specific action of the inducer in vivo . Increased Nrf2 activity alone was sufficient to protect animals from 3-NP toxicity because intrastriatal adenovirus-mediated
Nrf2 overexpression significantly reduced lesion size compared with green fluorescent protein overexpressing controls. In
cultured astrocytes, 3-NP was found to increase Nrf2 activity leading to antioxidant response element-dependent gene expression
providing a potential mechanism for the increased sensitivity of Nrf2 â/â animals to 3-NP toxicity in vivo . We conclude that Nrf2 may underlie a feedback system limiting oxidative load during chronic metabolic stress
Psychotic disorders are currently diagnosed by examining the patient's mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be ...useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.
NMDA receptors are activated after binding of the agonist glutamate to the NR2 subunit along with a co-agonist, either L-glycine or D-serine, to the NR1 subunit. There is substantial evidence to ...suggest that D-serine is the most relevant co-agonist in forebrain regions and that alterations in D-serine levels contribute to psychiatric disorders. D-serine is produced through isomerization of L-serine by serine racemase (Srr), either in neurons or in astrocytes. It is released by astrocytes by an activity-dependent mechanism involving secretory vesicles. In the present study we generated transgenic mice (SrrTg) expressing serine racemase under a human GFAP promoter. These mice were biochemically and behaviorally analyzed using paradigms of anxiety, depression and cognition. Furthermore, we investigated the behavioral effects of long-term administration of D-serine added to the drinking water. Elevated brain D-serine levels in SrrTg mice resulted in specific behavioral phenotypes in the forced swim, novelty suppression of feeding and olfactory bulbectomy paradigms that are indicative of a reduced proneness towards depression-related behavior. Chronic dietary D-serine supplement mimics the depression-related behavioral phenotype observed in SrrTg mice. Our results suggest that D-serine supplementation may improve mood disorders.
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.
The kynurenine pathway (KP) is gaining attention in several clinical fields. Recent studies show that physical exercise offers a therapeutic way to improve ratios of neurotoxic to neuroprotective KP ...metabolites. Antioxidant supplementation can blunt beneficial responses to physical exercise. We here studied the effects of endurance training in the form of sprint interval training (SIT; three sessions of 4–6 × 30 s cycling sprints per week for three weeks) in elderly (~65 years) men exposed to either placebo (n = 9) or the antioxidants vitamin C (1 g/day) and E (235 mg/day) (n = 11). Blood samples and muscle biopsies were taken under resting conditions in association with the first (untrained state) and last (trained state) SIT sessions. In the placebo group, the blood plasma level of the neurotoxic quinolinic acid was lower (~30%) and the neuroprotective kynurenic acid to quinolinic acid ratio was higher (~50%) in the trained than in the untrained state. Moreover, muscle biopsies showed a training-induced increase in kynurenine aminotransferase (KAT) III in the placebo group. All these training effects were absent in the vitamin-treated group. In conclusion, KP metabolism was shifted towards neuroprotection after three weeks of SIT in elderly men and this shift was blocked by antioxidant treatment.
Impaired sensorimotor gating, commonly measured as disrupted prepulse inhibition (PPI) of the acoustic startle response, has been widely observed in psychotic diseases. However, most PPI studies ...published so far involve patients with long illness duration and different drug treatments. Few studies have investigated untreated patients at their first episode of psychotic symptoms.
PPI is an acoustic startle paradigm (30, 60-, 120-ms interstimulus intervals). Startle reactivity and habituation were succesfully assessed in 49 antipsychotic-naïve first-episode psychosis (FEP) patients and compared with 35 age- and gender-matched healthy control subjects. Mean age of patients was 28 years and 27 for controls. Patients treated with antipsychotics more than 30 days were not included in the study and twenty-three out of forty-nine patients received antipsychotic treatment with a mean treatment time of 13 days.
PPI was significantly lower in FEP patients, compared to healthy controls. The PPI deficiency found in these patients was not due to antipsychotic treatment since PPI did not differ between treated (n=23) and untreated patients n=(26). By using the latent curve modeling we identified a delayed habituation in patients treated with antipsychotics, suggesting that antipsychotic treatment should be considered as a confound when investigating habituation in schizophrenia.
Our results suggest that acute pharmacological treatment does not normalize PPI in FEP patients but should be considered as a confound when investigating habituation in these patients.
PDF
