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Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring
Author(s) -
Khalil Omari S.,
Pisar Mazura,
Forrest Caroline M.,
Vincenten Maria C. J.,
Darlington L. Gail,
Stone Trevor W.
Publication year - 2014
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12535
Subject(s) - dentate gyrus , biology , dendritic spine , neun , kynurenic acid , hippocampal formation , nmda receptor , neurogenesis , glutamate receptor , kainic acid , quinolinic acid , microbiology and biotechnology , kynurenine pathway , ampa receptor , endocrinology , medicine , neuroscience , kynurenine , receptor , biochemistry , immunology , tryptophan , immunohistochemistry , amino acid
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 CA 1 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 CA 1 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.