Khalil Omari S, Pisar Mazura, Forrest Caroline M, Vincenten Maria C J, Darlington L Gail, Stone Trevor W
Institute of Neuroscience and Psychology, West Medical Building, University of Glasgow, Glasgow, G12 8QQ, UK.
Eur J Neurosci. 2014 May;39(10):1558-71. doi: 10.1111/ejn.12535. Epub 2014 Mar 19.
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.
N-甲基-D-天冬氨酸（NMDA）谷氨酸受体参与早期大脑发育。色氨酸代谢的犬尿氨酸途径包括NMDA受体激动剂喹啉酸和拮抗剂犬尿喹啉酸。我们现在报告，在大鼠孕期用3,4-二甲氧基-N-[4-(3-硝基苯基)噻唑-2-基]苯磺酰胺（Ro61-8048）抑制该途径，会使出生后60天的子代海马神经元形态、棘密度和发育蛋白的免疫细胞化学定位产生显著变化。高尔基-考克斯银染色显示，CA1区基底树突和二级基底树突的总数及长度减少，基底树突棘减少，基底树突分支的整体复杂性降低。齿状回颗粒细胞的树突也减少且复杂性降低。在CA1区和齿状回中检测到更多含有核标记NeuN和发育蛋白音猬因子的神经元。双皮质素染色显示，带有延长树突过程的新生颗粒细胞减少。Ro61-8048使囊泡谷氨酸转运体（VGLUT）-1和VGLUT-2染色的神经元终末数量增加，而囊泡GABA转运体的表达及其与囊泡相关膜蛋白-1的共定位没有变化。这些数据支持这样的观点，即组成型犬尿氨酸代谢通常在胚胎早期大脑发育中起作用，干扰它会对神经元结构和形态产生深远影响，并持续到成年期。
