Prenatal inhibition of the tryptophan-kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

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• 作者：Caroline M. Forrest^a ; ¹ ; Omari S. Khalil^a ; ¹ ; Mazura Pisar^a ; L. Gail Darlington^b ; Trevor W. Stone^a ; ^{Trevor.Stone@glasgow.ac.uk}
• 关键词：Kynurenines ; Kynurenic acid ; Tryptophan ; Neurodevelopment ; Rho proteins ; Sonic hedgehog ; Doublecortin
• 刊名：Brain Research
• 出版年：2013
• 出版时间：4 April, 2013
• 年：2013
• 卷：1504
• 期：Complete
• 页码：1-15
• 全文大小：785 K

文摘

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5 h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24 h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system.