title: Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine.
abstract: Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Forrest
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: K
authors.initials: K
authors.lastname: McNair
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pisar
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: O S
authors.initials: OS
authors.lastname: Khalil
authors.affiliation: Ashtead Hospital, The Warren, Ashtead, Surrey KT21 2SB, UK.
authors.forename: L G
authors.initials: LG
authors.lastname: Darlington
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: Trevor.Stone@glasgow.ac.uk.
authors.forename: T W
authors.initials: TW
authors.lastname: Stone
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000818:Animals; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005702:Galantamine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005865:Gestational Age; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D007737:Kynurenine / Q000494:pharmacology*; D050601:Kynurenine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology*; D011339:Probenecid / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism
chemical_list: D000277:Adjuvants, Pharmaceutic; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018697:Nootropic Agents; D017470:Receptors, Glutamate; D005702:Galantamine; D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase; D011339:Probenecid
keywords: kynurenic acid; kynurenines; neurodevelopment; tryptophan