title: Modified neocortical and cerebellar protein expression and morphology in adult rats following prenatal inhibition of the kynurenine pathway.
abstract: Inhibition of the kynurenine pathway of tryptophan metabolism during gestation can lead to changes in synaptic transmission, neuronal morphology and plasticity in the rat hippocampus. This suggests a role for the kynurenine pathway in early brain development, probably caused by kynurenine modulation of N-methyl-d-aspartate (NMDA) glutamate receptors which are activated by the tryptophan metabolite quinolinic acid and blocked by kynurenic acid. We have now examined samples of neocortex and cerebellum of adult animals to assess the effects of a prenatally administered kynurenine-3-monoxygenase inhibitor (Ro61-8048) on protein and mRNA expression, dendritic structure and immuno-histochemistry. No changes were seen in mRNA expression using quantitative real-time polymerase chain reaction. Changes were detected in the expression of several proteins including the GluN2A subunit, unco-ordinated-5H3 (unc5H3), doublecortin, cyclo-oxygenase, sonic hedgehog and Disrupted in schizophrenia-1 (DISC1), although no differences in immunoreactive cell numbers were observed. In the midbrain, dependence receptor expression was also changed. The numbers and lengths of individual dendritic regions were not changed but there were significant increases in the overall complexity values of apical and basal dendritic trees. The data support the hypothesis that constitutive kynurenine metabolism plays a critical role in early, embryonic brain development, although fewer effects are produced in the neocortex and cerebellum than in the hippocampus and the nature of the changes seen are qualitatively different. The significant changes in DISC1 and unc5H3 may be relevant to cerebellar dysfunction and schizophrenia respectively, in which these proteins have been previously implicated.
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Mazura
authors: M
authors: Pisar
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Caroline M
authors: CM
authors: Forrest
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Omari S
authors: OS
authors: Khalil
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Kara
authors: K
authors: McNair
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Maria C J
authors: MC
authors: Vincenten
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors: Susana
authors: S
authors: Qasem
authors: Ashtead Hospital, The Warren, Ashtead, Surrey KT11 2SB, UK.
authors: L Gail
authors: LG
authors: Darlington
authors: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: Trevor.Stone@glasgow.ac.uk.
authors: Trevor W
authors: TW
authors: Stone
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D003712:Dendrites / Q000648:ultrastructure; D000089662:Doublecortin Protein; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D019579:Neocortex / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects*; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D009435:Synaptic Transmission; D013844:Thiazoles / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D007737:Kynurenine; D014364:Tryptophan; D050601:Kynurenine 3-Monooxygenase
keywords: Doublecortin; GABA transport; Glutamate transport; Kynurenic acid; Kynurenines; Neurodevelopment; Sonic hedgehog