NMDA and non-NMDA receptor-mediated excitotoxicity are potentiated in cultured striatal neurons by prior chronic depolarization
NMDA and non-NMDA receptor-mediated excitotoxicity are potentiated in cultured striatal neurons by prior chronic depolarization
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DOI：
10.1006/exnr.1999.7135
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发表时间：
1999-09-01
影响因子：
5.3
通讯作者：
Reiner, A
中科院分区：
文献类型：
--
作者：
Chen, Q;Surmeier, DJ;Reiner, A
从皮质和/或丘脑到纹状体的兴奋性输入似乎促进了纹状体神经元上谷氨酸受体的成熟，但其作用机制尚不清楚。为了探讨纹状体的兴奋性输入可能影响纹状体神经元谷氨酸受体成熟的可能性，至少部分通过其对纹状体神经元的去极化作用，我们研究了慢性KCl去极化对谷氨酸受体介导的兴奋性毒性脆弱性和培养的纹状体神经元中谷氨酸受体的发展的影响。将来自 E17 大鼠胚胎的分离纹状体神经元在含有低 (3 mM) 或高 (25 mM) KCl 的 Barrett 培养基中培养 2 周。通过监测激动剂暴露 1 小时后 24 小时的细胞损失，检查这些神经元对 NMDA 受体激动剂（NMDA 和喹啉酸）、非 NMDA 受体激动剂（AMPA 和 KA）和代谢型谷氨酸受体激动剂（反式 ACPD）的脆弱性。我们发现，高 KCl 培养增强了用 500 μM NMDA 或 250 μM KA 观察到的细胞损失，而用 250 μM AMPA 产生的细胞损失在低 KCl 培养下并不明显。相比之下，高达 5 mM 的 QA 和反式 ACPD 在任一 KCl 组中均没有显着的毒性作用。 ELISA 显示，长期高 KCI 使培养的纹状体神经元上的 NMDA NR2A/B、AMPA GluR2/3 和 KA GluR5-7 受体亚基丰度增加一倍，并使 AMPA GluR1 和 GluR4 亚基增加一倍以上，但对 NMDA NR1 亚基水平没有影响。这些受体的变化可能有助于这些神经元在长期高 KCl 饲养后表现出的 NMDA 和非 NMDA 受体介导的兴奋性毒性的增强。我们的研究表明，皮质纹状体和/或丘脑纹状体神经支配产生的膜去极化可能是纹状体神经元上谷氨酸受体成熟所必需的，并且这种成熟可能对于纹状体神经元的 NMDA 表达和非 NMDA 受体介导的兴奋性毒性很重要。因此，在长期去极化条件下培养的纹状体培养物可能提供更合适的培养模型来研究 NMDA 或非 NMDA 受体亚型在纹状体兴奋性毒性中的作用（1999 年学术出版社）。
The excitatory input from cortex and/or thalamus to striatum appears to promote the maturation of glutamate receptors on striatal neurons, but the mechanisms by which it does so have been uncertain. To explore the possibility that the excitatory input to striatum might influence glutamate receptor maturation on striatal neurons, at least in part, by its depolarizing effect on striatal neurons, we examined the influence of chronic KCl depolarization on the development of glutamate receptor-mediated excitotoxic vulnerability and glutamate receptors in cultured striatal neurons. Dissociated striatal neurons from E17 rat embryos were cultured for 2 weeks in Barrett's medium containing either low (3 mM) or high (25 mM) KCl. The vulnerability of these neurons to NMDA receptor agonists (NMDA and quinolinic acid), non-NMDA receptor agonists (AMPA and KA), and a metabotropic glutamate receptor agonist (trans-ACPD) was examined by monitoring cell loss 24 h after a 1-h agonist exposure. We found that high-KCl rearing potentiated the cell loss observed with 500 mu M NMDA or 250 mu M KA and yielded cell loss with 250 mu M AMPA that was not evident under low KCl rearing. In contrast, neither QA up to 5 mM nor trans-ACPD had a significant toxic effect in either KCl group. ELISA revealed that chronic high KCI doubled the abundance of NMDA NR2A/B, AMPA GluR2/3, and KA GluR5-7 receptor subunits on cultured striatal neurons and more than doubled AMPA GluR1 and GluR4 subunits, but had no effect on NMDA NR1 subunit levels. These receptor changes may contribute to the potentiation of NMDA and non-NMDA receptor-mediated excitotoxicity shown by these neurons following chronic high-KCl rearing. Our studies suggest that membrane depolarization produced by corticostriatal and/or thalamostriatal innervation may be required for maturation of glutamate receptors on striatal neurons, and such maturation may be important for expression of NMDA and non-NMDA receptor-mediated excitotoxicity by striatal neurons. Striatal cultures raised under chronically depolarized conditions may, thus, provide a more appropriate culture model to study the role of NMDA or non-NMDA receptor subtypes in excitotoxicity in striatum, a 1999 Academic Press.