Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

Biological Psychiatry

Volumn 82, Issue 10, 2017, Pages 756-765

  Erhardt, Sophie ^a   Pocivavsek, Ana ^b   Repici, Mariaelena ^c   Liu, Xi Cong ^a   Imbeault, Sophie ^a   Maddison, Daniel C ^c   Thomas, Marian A R ^b   Smalley, Joshua L ^c   Larsson, Markus K ^a   Muchowski, Paul J ^d   Giorgini, Flaviano ^c   Schwarcz, Robert ^b  

^a KAROLINSKA INSTITUTE   (Sweden)

^b UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF LEICESTER   (United Kingdom)

^d KynuRex   (United States)

Author keywords

Anxiety; Cognition; Kynurenic acid; Locomotor activity; Schizophrenia; Social interaction

Indexed keywords

DEXAMPHETAMINE; KYNURENIC ACID; KYNURENINE 3 MONOOXYGENASE;

ADAPTIVE BEHAVIOR; ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANXIETY; ARTICLE; BEHAVIOR CHANGE; BRAIN; BRAIN CORTEX; BRAIN REGION; CEREBELLUM; CONTROLLED STUDY; GENE EXPRESSION; KNOCKOUT MOUSE; LATENT PERIOD; LOCOMOTION; MALE; MOUSE; NONHUMAN; OPEN FIELD TEST; PASSIVE AVOIDANCE; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; QUANTITATIVE ANALYSIS; REAL TIME POLYMERASE CHAIN REACTION; SCHIZOPHRENIA; SOCIAL INTERACTION; ANIMAL; DEFICIENCY; DRUG EFFECT; GENETICS; METABOLISM; MOTOR ACTIVITY; PHYSIOLOGY; PSYCHOLOGY; PSYCHOSIS;

ANIMALS; CEREBELLUM; CEREBRAL CORTEX; DEXTROAMPHETAMINE; KYNURENIC ACID; KYNURENINE 3-MONOOXYGENASE; MICE; MICE, KNOCKOUT; MOTOR ACTIVITY; PSYCHOTIC DISORDERS; SCHIZOPHRENIA; SCHIZOPHRENIC PSYCHOLOGY;

EID: 85011565078     PISSN: 00063223     EISSN: 18732402     Source Type: Journal    
DOI: 10.1016/j.biopsych.2016.12.011     Document Type: Article

References (81)

1. Colin-Gonzalez, A.L., Maldonado, P.D., Santamariá, A., 3-Hydroxykynurenine: An intriguing molecule exerting dual actions in the central nervous system. Neurotoxicology 34 (2013), 189–204.
2. Parrott, J.M., O׳Connor, J.C., Kynurenine 3-monooxygenase: An influential mediator of neuropathology. Front Psychiatry, 6, 2015, 116.
3. Lavebratt, C., Olsson, S., Backlund, L., Frisen, L., Sellgren, C., Priebe, L., et al. The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol Psychiatry 19 (2014), 334–341.
4. Sathyasaikumar, K.V., Stachowski, E.K., Wonodi, I., Roberts, R.C., Rassoulpour, A., McMahon, R.P., et al. Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. Schizophr Bull 37 (2011), 1147–1156.
5. Wonodi, I., Schwarcz, R., Cortical kynurenine pathway metabolism: A novel target for cognitive enhancement in schizophrenia. Schizophr Bull 36 (2010), 211–218.
6. Carpenter, W.T. Jr., Buchanan, R.W., Schizophrenia. N Engl J Med 330 (1994), 681–690.
7. Wonodi, I., Stine, O.C., Sathyasaikumar, K.V., Roberts, R.C., Mitchell, B.D., Hong, L.E., et al. Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. Arch Gen Psychiatry 68 (2011), 665–674.
8. Schwarcz, R., Rassoulpour, A., Wu, H.Q., Medoff, D., Tamminga, C.A., Roberts, R.C., Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50 (2001), 521–530.
9. Aoyama, N., Takahashi, N., Saito, S., Maeno, N., Ishihara, R., Ji, X., et al. Association study between kynurenine 3-monooxygenase gene and schizophrenia in the Japanese population. Genes Brain Behav 5 (2006), 364–368.
10. Erhardt, S., Blennow, K., Nordin, C., Skogh, E., Lindstrom, L.H., Engberg, G., Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 313 (2001), 96–98.
11. Linderholm, K.R., Skogh, E., Olsson, S.K., Dahl, M.L., Holtze, M., Engberg, G., et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull 38 (2012), 426–432.
12. Miller, C.L., Llenos, I.C., Dulay, J.R., Weis, S., Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder. Brain Res 1073–1074 (2006), 25–37.
13. Nilsson, L.K., Linderholm, K.R., Engberg, G., Paulson, L., Blennow, K., Lindstrom, L.H., et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80 (2005), 315–322.
14. Olsson, S.K., Samuelsson, M., Saetre, P., Lindstrom, L., Jonsson, E.G., Nordin, C., et al. Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. J Psychiatry Neurosci 35 (2010), 195–199.
15. Sellgren, C.M., Kegel, M.E., Bergen, S.E., Ekman, C.J., Olsson, S., Larsson, M., et al. A genome-wide association study of kynurenic acid in cerebrospinal fluid: Implications for psychosis and cognitive impairment in bipolar disorder. Mol Psychiatry 21 (2015), 1342–1350.
16. Carpenedo, R., Chiarugi, A., Russi, P., Lombardi, G., Carlà, V., Pellicciari, R., et al. Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience 61 (1994), 237–243.
17. Speciale, C., Wu, H.Q., Cini, M., Marconi, M., Varasi, M., Schwarcz, R., (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. Eur J Pharmacol 315 (1996), 263–267.
18. Zwilling, D., Huang, S.Y., Sathyasaikumar, K.V., Notarangelo, F.M., Guidetti, P., Wu, H.Q., et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145 (2011), 863–874.
19. Giorgini, F., Huang, S.Y., Sathyasaikumar, K.V., Notarangelo, F.M., Thomas, M.A., Tararina, M., et al. Targeted deletion of kynurenine 3-monooxygenase in mice: A new tool for studying kynurenine pathway metabolism in periphery and brain. J Biol Chem 288 (2013), 36554–36566.
20. Hilmas, C., Pereira, E.F., Alkondon, M., Rassoulpour, A., Schwarcz, R., Albuquerque, E.X., The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21 (2001), 7463–7473.
21. Birch, P.J., Grossman, C.J., Hayes, A.G., Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. Eur J Pharmacol 154 (1988), 85–87.
22. Ganong, A.H., Cotman, C.W., Kynurenic acid and quinolinic acid act at N-methyl-D-aspartate receptors in the rat hippocampus. J Pharmacol Exp Ther 236 (1986), 293–299.
23. Kessler, M., Terramani, T., Lynch, G., Baudry, M., A glycine site associated with N-methyl-D-aspartic acid receptors: Characterization and identification of a new class of antagonists. J Neurochem 52 (1989), 1319–1328.
24. Lin, H., Hsu, F.C., Baumann, B.H., Coulter, D.A., Lynch, D.R., Cortical synaptic NMDA receptor deficits in alpha7 nicotinic acetylcholine receptor gene deletion models: implications for neuropsychiatric diseases. Neurobiol Dis 63 (2014), 129–140.
25. Koola, M.M., Buchanan, R.W., Pillai, A., Aitchison, K.J., Weinberger, D.R., Aaronson, S.T., et al. Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia. Schizophr Res 157 (2014), 84–89.
26. Moroni, F., Cozzi, A., Sili, M., Mannaioni, G., Kynurenic acid: A metabolite with multiple actions and multiple targets in brain and periphery. J Neural Transm (Vienna) 119 (2012), 133–139.
27. Stone, T.W., Stoy, N., Darlington, L.G., An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34 (2013), 136–143.
28. Erhardt, S., Schwieler, L., Emanuelsson, C., Geyer, M., Endogenous kynurenic acid disrupts prepulse inhibition. Biol Psychiatry 56 (2004), 255–260.
29. Shepard, P.D., Joy, B., Clerkin, L., Schwarcz, R., Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat. Neuropsychopharmacology 28 (2003), 1454–1462.
30. Chess, A.C., Simoni, M.K., Alling, T.E., Bucci, D.J., Elevations of endogenous kynurenic acid produce spatial working memory deficits. Schizophr Bull 33 (2007), 797–804.
31. Chess, A.C., Landers, A.M., Bucci, D.J., L-kynurenine treatment alters contextual fear conditioning and context discrimination but not cue-specific fear conditioning. Behav Brain Res 201 (2009), 325–331.
32. Pocivavsek, A., Wu, H.Q., Potter, M.C., Elmer, G.I., Pellicciari, R., Schwarcz, R., Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36 (2011), 2357–2367.
33. Alexander, K.S., Wu, H.Q., Schwarcz, R., Bruno, J.P., Acute elevations of brain kynurenic acid impair cognitive flexibility: Normalization by the alpha7 positive modulator galantamine. Psychopharmacology (Berl) 220 (2012), 627–637.
34. Smalley, J.L., Breda, C., Mason, R.P., Kooner, G., Luthi-Carter, R., Gant, T.W., et al. Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington׳s disease models. J Mol Med (Berl) 94 (2016), 235–245.
35. Varadarajan, S., Bampton, E.T., Smalley, J.L., Tanaka, K., Caves, R.E., Butterworth, M., et al. A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum. Cell Death Differ 19 (2012), 1896–1907.
36. Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., et al. STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43 (2015), D447–D452.
37. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., et al. Common variants conferring risk of schizophrenia. Nature 460 (2009), 744–747.
38. Pak, J.H., Huang, F.L., Li, J., Balschun, D., Reymann, K.G., Chiang, C., et al. Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: A study with knockout mice. Proc Natl Acad Sci U S A 97 (2000), 11232–11237.
39. Yamada, K., Gerber, D.J., Iwayama, Y., Ohnishi, T., Ohba, H., Toyota, T., et al. Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3, as potential susceptibility candidates in schizophrenia. Proc Natl Acad Sci U S A 104 (2007), 2815–2820.
40. Poirier, R., Cheval, H., Mailhes, C., Garel, S., Charnay, P., Davis, S., et al. Distinct functions of egr gene family members in cognitive processes. Front Neurosci 2 (2008), 47–55.
41. Murakami, G., Hunter, R.G., Fontaine, C., Ribeiro, A., Pfaff, D., Relationships among estrogen receptor, oxytocin and vasopressin gene expression and social interaction in male mice. Eur J Neurosci 34 (2011), 469–477.
42. Haram, M., Tesli, M., Bettella, F., Djurovic, S., Andreassen, O.A., Melle, I., Association between genetic variation in the oxytocin receptor gene and emotional withdrawal, but not between oxytocin pathway genes and diagnosis in psychotic disorders. Front Hum Neurosci, 9, 2015, 9.
43. Jentsch, J.D., Arguello, P.A., Anzivino, L.A., Null mutation of the arginine-vasopressin gene in rats slows attentional engagement and facilitates response accuracy in a lateralized reaction time task. Neuropsychopharmacology 28 (2003), 1597–1605.
44. Li, D., He, L., G72/G30 genes and schizophrenia: A systematic meta-analysis of association studies. Genetics 175 (2007), 917–922.
45. Uwai, Y., Hara, H., Iwamoto, K., Transport of kynurenic acid by rat organic anion transporters rOAT1 and rOAT3: Species difference between human and rat in OAT1. Int J Tryptophan Res 6 (2013), 1–6.
46. Oxenkrug, G., van der Hart, M., Roeser, J., Summergrad, P., Anthranilic acid: A potential biomarker and treatment target for schizophrenia. Ann Psychiatry Ment Health, 4, 2016.
47. Miller, C.L., Llenos, I.C., Cwik, M., Walkup, J., Weis, S., Alterations in kynurenine precursor and product levels in schizophrenia and bipolar disorder. Neurochem Int 52 (2008), 1297–1303.
48. Hiramatsu, R., Hara, T., Akimoto, H., Takikawa, O., Kawabe, T., Isobe, K., et al. Cinnabarinic acid generated from 3-hydroxyanthranilic acid strongly induces apoptosis in thymocytes through the generation of reactive oxygen species and the induction of caspase. J Cell Biochem 103 (2008), 42–53.
49. Pocivavsek, A., Thomas, M.A., Elmer, G.I., Bruno, J.P., Schwarcz, R., Continuous kynurenine administration during the prenatal period, but not during adolescence, causes learning and memory deficits in adult rats. Psychopharmacology (Berl) 231 (2014), 2799–2809.
50. Pocivavsek, A., Wu, H.Q., Elmer, G.I., Bruno, J.P., Schwarcz, R., Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur J Neurosci 35 (2012), 1605–1612.
51. Albuquerque, E.X., Schwarcz, R., Kynurenic acid as an antagonist of alpha7 nicotinic acetylcholine receptors in the brain: Facts and challenges. Biochem Pharmacol 85 (2013), 1027–1032.
52. Yang, M., Silverman, J.L., Crawley, J.N., Automated three-chambered social approach task for mice. Curr Protoc Neurosci, 2011 Chapter 8:Unit 8.26.
53. Iaccarino, H.F., Suckow, R.F., Xie, S., Bucci, D.J., The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia. Schizophr Res 150 (2013), 392–397.
54. Trecartin, K.V., Bucci, D.J., Administration of kynurenine during adolescence, but not during adulthood, impairs social behavior in rats. Schizophr Res 133 (2011), 156–158.
55. McFarlane, H.G., Kusek, G.K., Yang, M., Phoenix, J.L., Bolivar, V.J., Crawley, J.N., Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7 (2008), 152–163.
56. Olsson, S.K., Larsson, M.K., Erhardt, S., Subchronic elevation of brain kynurenic acid augments amphetamine-induced locomotor response in mice. J Neural Transm (Vienna) 119 (2012), 155–163.
57. Salazar, A., Gonzalez-Rivera, B.L., Redus, L., Parrott, J.M., O׳Connor, J.C., Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav 62 (2012), 202–209.
58. Vécsei, L., Beal, M.F., Influence of kynurenine treatment on open-field activity, elevated plus maze, avoidance behaviors and seizures in rats. Pharmacol Biochem Behav 37 (1990), 71–76.
59. Goldstein, M., Deutch, A.Y., Dopaminergic mechanisms in the pathogenesis of schizophrenia. FASEB J 6 (1992), 2413–2421.
60. Geyer, M.A., Krebs-Thomson, K., Braff, D.L., Swerdlow, N.R., Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: A decade in review. Psychopharmacology (Berl) 156 (2001), 117–154.
61. Nilsson, L.K., Linderholm, K.R., Erhardt, S., Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons. J Neural Transm (Vienna) 113 (2006), 557–571.
62. Hasenkamp, W., Kelley, M., Egan, G., Green, A., Wilcox, L., Boshoven, W., et al. Lack of relationship between acoustic startle and cognitive variables in schizophrenia and control subjects. Psychiatry Res 187 (2011), 324–328.
63. Erhardt, S., Schwieler, L., Imbeault, S., Engberg, G., The kynurenine pathway in schizophrenia and bipolar disorder. Neuropharmacology 112 (2017), 297–306.
64. Pocivavsek, A., Notarangelo, F.M., Wu, H.Q., Bruno, J.P., Schwarcz, R., Astrocytes as pharmacological targets in the treatment of schizophrenia: focus on kynurenic acid. Pletnikov, M.V., Waddington, J.L., (eds.) Modeling the Psychophathological Dimensions of Schizophrenia - From Molecules to Behavior, 2016, Elsevier, New York, 423–443.
65. Volk, D.W., Lewis, D.A., Prefrontal cortical circuits in schizophrenia. Curr Top Behav Neurosci 4 (2010), 485–508.
66. Baran, H., Schwarcz, R., Regional differences in the ontogenetic pattern of kynurenine aminotransferase in the rat brain. Brain Res Dev Brain Res 74 (1993), 283–286.
67. Blanco Ayala, T., Lugo Huítron, R., Carmona Aparicio, L., Ramirez Ortega, D., Gonzalez Esquivel, D., Pedraza Chaverri, J., et al. Alternative kynurenic acid synthesis routes studied in the rat cerebellum. Front Cell Neurosci, 9, 2015, 178.
68. Kanai, M., Nakamura, T., Funakoshi, H., Identification and characterization of novel variants of the tryptophan 2,3-dioxygenase gene: Differential regulation in the mouse nervous system during development. Neurosci Res 64 (2009), 111–117.
69. Notarangelo, F.M., Pocivavsek, A., Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior. Neuropharmacology 112 (2017), 275–285.
70. Wu, H.Q., Schwarcz, R., Modulation of glutamate and dopamine levels in the prefrontal cortex by intra-cerebellar kynurenic acid infusion in the rat. Soc Neurosci Abstr, 38, 2013, 231.03.
71. Andreasen, N.C., Pierson, R., The role of the cerebellum in schizophrenia. Biol Psychiatry 64 (2008), 81–88.
72. Hensch, T.K., Critical period mechanisms in developing visual cortex. Curr Top Dev Biol 69 (2005), 215–237.
73. Huntley, G.W., Vickers, J.C., Morrison, J.H., Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: Organizational features related to cortical circuitry, function and disease. Trends Neurosci 17 (1994), 536–543.
74. Lozada, A.F., Wang, X., Gounko, N.V., Massey, K.A., Duan, J., Liu, Z., et al. Glutamatergic synapse formation is promoted by alpha7-containing nicotinic acetylcholine receptors. J Neurosci 32 (2012), 7651–7661.
75. Russo, P., Taly, A., α7-Nicotinic acetylcholine receptors: An old actor for new different roles. Curr Drug Targets 13 (2012), 574–578.
76. Ultanir, S.K., Kim, J.E., Hall, B.J., Deerinck, T., Ellisman, M., Ghosh, A., Regulation of spine morphology and spine density by NMDA receptor signaling in vivo. Proc Natl Acad Sci U S A 104 (2007), 19553–19558.
77. Beggiato, S., Sathyasaikumar, K.V., Notarangelo, F.M., Giorgini, F., Muchowski, J.M., Schwarcz, R., Prenatal kynurenine treatment in mice: Effects on placental and fetal brain kynurenines. Soc Neurosci Abstr, 39, 2014, 51.05.
78. Pocivavsek, A., Thomas, M.A., Giorgini, F., Schwarcz, R., Targeted deletion of both kynurenine aminotransferase II and kynurenine 3-monooxygenase in mice: Implications for studying kynurenine pathway metabolism. Soc Neurosci Abstr, 41, 2016, 364.03.
79. Wu, H.Q., Okuyama, M., Kajii, Y., Pocivavsek, A., Bruno, J.P., Schwarcz, R., Targeting kynurenine aminotransferase II in psychiatric diseases: Promising effects of an orally active enzyme inhibitor. Schizophr Bull 40:suppl 2 (2014), S152–S158.
80. Kohl, P., Crampin, E.J., Quinn, T.A., Noble, D., Systems biology: An approach. Clin Pharmacol Ther 88 (2010), 25–33.
81. Erhardt, S., Olsson, S.K., Engberg, G., Pharmacological manipulation of kynurenic acid: potential in the treatment of psychiatric disorders. CNS Drugs 23 (2009), 91–101.