title: Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring.
abstract: Glutamate receptors for N-methyl-d-aspartate (NMDA) are involved in early brain development. The kynurenine pathway of tryptophan metabolism includes the NMDA receptor agonist quinolinic acid and the antagonist kynurenic acid. We now report that prenatal inhibition of the pathway in rats with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulphonamide (Ro61-8048) produces marked changes in hippocampal neuron morphology, spine density and the immunocytochemical localisation of developmental proteins in the offspring at postnatal day 60. Golgi-Cox silver staining revealed decreased overall numbers and lengths of CA1 basal dendrites and secondary basal dendrites, together with fewer basal dendritic spines and less overall dendritic complexity in the basal arbour. Fewer dendrites and less complexity were also noted in the dentate gyrus granule cells. More neurons containing the nuclear marker NeuN and the developmental protein sonic hedgehog were detected in the CA1 region and dentate gyrus. Staining for doublecortin revealed fewer newly generated granule cells bearing extended dendritic processes. The number of neuron terminals staining for vesicular glutamate transporter (VGLUT)-1 and VGLUT-2 was increased by Ro61-8048, with no change in expression of vesicular GABA transporter or its co-localisation with vesicle-associated membrane protein-1. These data support the view that constitutive kynurenine metabolism normally plays a role in early embryonic brain development, and that interfering with it has profound consequences for neuronal structure and morphology, lasting into adulthood.
authors.affiliation: Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, UK.
authors.forename: Omari S
authors.initials: OS
authors.lastname: Khalil
authors.forename: Mazura
authors.initials: M
authors.lastname: Pisar
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Forrest
authors.forename: Maria C J
authors.initials: MC
authors.lastname: Vincenten
authors.forename: L Gail
authors.initials: LG
authors.lastname: Darlington
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Stone
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology* / Q000503:physiopathology; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D050987:Vesicle-Associated Membrane Protein 1 / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004791:Enzyme Inhibitors; D053823:Hedgehog Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C546339:Rbfox3 protein, rat; C110196:Ro 61-8048; C546888:Shh protein, rat; C493475:Slc17a6 protein, rat; C493466:Slc17a7 protein, rat; C118623:Slc32a1 protein, rat; D013449:Sulfonamides; D013844:Thiazoles; D050987:Vesicle-Associated Membrane Protein 1; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C494705:vesicle-associated membrane protein 1, rat; D007737:Kynurenine
keywords: GABA transport; doublecortin; glutamate transport; kynurenic acid; neurodevelopment; sonic hedgehog