N-Methyl D-Aspartate Receptor Antagonist Kynurenic Acid Affects Human Cortical Development.
N-Methyl D-Aspartate Receptor Antagonist Kynurenic Acid Affects Human Cortical Development.
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DOI：
10.3389/fnins.2016.00435
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发表时间：
2016
影响因子：
4.3
通讯作者：
Radonjić NV
中科院分区：
文献类型：
--
作者：
Bagasrawala I;Zecevic N;Radonjić NV
犬尿烯酸（KYNA）是色氨酸降解的神经活性代谢产物，是一种内源性N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂。在病毒感染后的孕妇中观察到KYNA水平升高，并被认为在神经发育障碍中发挥作用。然而，KYNA诱导的NMDAR阻断在人类皮质发育中的后果仍然难以捉摸。为了研究KYNA对人类神经发育的潜在影响，我们使用了多能皮质祖细胞的体外系统，即，放射状胶质细胞（RGC），从妊娠中期（16-19孕周）的人类大脑皮质富集。KYNA处理通过拮抗NMDAR显著降低RGCs增殖和存活。这种改变导致皮质祖细胞和神经元的数量减少，而星形胶质细胞的数量和活化增加。KYNA处理减少了RGC向GABA能神经元的分化，而向谷氨酸能神经元的分化相对较少。此外，在混合的皮质培养物中，KYNA引发了炎症反应，如促炎细胞因子IL-6水平增加所证明的。总之，KYNA水平升高通过拮抗NMDAR和激活炎症反应在人RGC命运决定中起重要作用。在暴露于升高的KYNA水平后在细胞培养物中观察到的细胞组成改变表明病毒感染后胎儿脑中皮质回路形成受损的机制，如在神经发育障碍如精神分裂症中所见。
Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation, acts as an endogenous N-methyl-D-aspartate receptor (NMDAR) antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and are considered to play a role in neurodevelopmental disorders. However, the consequences of KYNA-induced NMDAR blockade in human cortical development still remain elusive. To study the potential impact of KYNA on human neurodevelopment, we used an in vitro system of multipotent cortical progenitors, i.e., radial glia cells (RGCs), enriched from human cerebral cortex at mid-gestation (16–19 gestational weeks). KYNA treatment significantly decreased RGCs proliferation and survival by antagonizing NMDAR. This alteration resulted in a reduced number of cortical progenitors and neurons while number and activation of astrocytes increased. KYNA treatment reduced differentiation of RGCs into GABAergic neurons, while differentiation into glutamatergic neurons was relatively spared. Furthermore, in mixed cortical cultures KYNA triggered an inflammatory response as evidenced by increased levels of the pro-inflammatory cytokine IL-6. In conclusion, elevated levels of KYNA play a significant role in human RGC fate determination by antagonizing NMDARs and by activating an inflammatory response. The altered cell composition observed in cell culture following exposure to elevated KYNA levels suggests a mechanism for impairment of cortical circuitry formation in the fetal brain after viral infection, as seen in neurodevelopmental disorders such as schizophrenia.
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DOI：
10.1038/npp.2012.248
发表时间：
2013-04
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
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早期生活节目和神经发育障碍。
影响因子：
10.6
作者：
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通讯作者：
Nestler, Eric J.
影响因子：
2.5
作者：
Erhardt, S;Blennow, K;Engberg, G
通讯作者：
Engberg, G
影响因子：
7.6
作者：
Garver, DL;Tamas, RL;Holcomb, JA
通讯作者：
Holcomb, JA
DOI：
10.1111/j.1460-9568.2008.06475.x
发表时间：
2008-10
期刊：
The European journal of neuroscience
影响因子：
--
作者：
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通讯作者：
Clowry GJ