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.
Highlights
There is increasing evidence to suggest that the earliest stages of brain development in utero may be susceptible to modification by environmental factors, including diet, stress, and infection, which affect the rate of brain development overall or the relative development of different brain regions, leading to the appearance of disorders such as schizophrenia in postnatal life (Meyer & Feldon, 2010; Brown, 2011)
The results indicate that prenatal inhibition of the kynurenine pathway produces marked effects on neuronal structure and development, suggesting that the pathway is constitutively active in the embryo and contributes to the regulation of early brain development
When Ro61-8048 and other KMO inhibitors are administered to adult animals, their major effect is to increase the levels of kynurenic acid in the blood and tissues (Chiarugi et al, 1995; Speciale et al, 1996; R€over et al, 1997; Cozzi et al, 1999; Clark et al, 2005), including at least 10-fold elevations in brain microdialysates in vivo (Urenjak & Obrenovitch, 2000) In the present study, Ro618048 was administered to pregnant rats at a dose that has been shown to increase kynurenic acid levels in the blood and brain of the pregnant dam and the brains of the embryos
Summary
There is increasing evidence to suggest that the earliest stages of brain development in utero may be susceptible to modification by environmental factors, including diet, stress, and infection, which affect the rate of brain development overall or the relative development of different brain regions, leading to the appearance of disorders such as schizophrenia in postnatal life (Meyer & Feldon, 2010; Brown, 2011). The oxidation of tryptophan to kynurenine leads to the generation of two compounds with known activity at N-methyl-D-aspartate (NMDA) receptors. These are quinolinic acid, an agonist selective for NMDA receptors (Stone & Perkins, 1981; Stone, 2001), and. Kynurenic acid may block nicotinic cholinoceptors (Hilmas et al, 2001), others have failed to confirm this observation (Mok et al.,2009; Dobelis et al, 2012)
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