O.S.K. and M.P. contributed equally to this work.
Prenatal inhibition of the kynurenine pathway leads to structural changes in the hippocampus of adult rat offspring
Article first published online: 19 MAR 2014
© 2014 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
European Journal of Neuroscience
Volume 39, Issue 10, pages 1558–1571, May 2014
How to Cite
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: 1558–1571. doi: 10.1111/ejn.12535
[Correction added on 28 May 2014, after first online publication: article was made open access].
- Issue published online: 18 MAY 2014
- Article first published online: 19 MAR 2014
- Manuscript Accepted: 30 JAN 2014
- Manuscript Revised: 28 JAN 2014
- Manuscript Received: 4 NOV 2013
- Malaysian Government
- Epsom Medical Research
- Peacock Trust
- Haddon Family Trust
- GABA transport;
- glutamate transport;
- kynurenic acid;
- sonic hedgehog
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.