Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring

Khalil, O. S., Pisar, M., Forrest, C. M., Vincenten, M. C. J., Darlington, L. G. and Stone, T. W. (2014) Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring. European Journal of Neuroscience, 39(10), pp. 1558-1571. (doi: 10.1111/ejn.12535)

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Publisher's URL: http://dx.doi.org/10.1111/ejn.12535

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Forrest, Dr Caroline and Stone, Professor Trevor and Vincenten, Miss Maria
Authors: Khalil, O. S., Pisar, M., Forrest, C. M., Vincenten, M. C. J., Darlington, L. G., and Stone, T. W.
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:European Journal of Neuroscience
Journal Abbr.:Europ. J. Neurosci.
Publisher:Wiley
ISSN:0953-816X
ISSN (Online):1460-9568
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in European Journal of Neuroscience 39(10):1558-1571
Publisher Policy:Reproduced under a Creative Commons License

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