Noh Kyung-Min, Yokota Hidenori, Mashiko Toshihiro, Castillo Pablo E, Zukin R Suzanne, Bennett Michael V L
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12230-5. doi: 10.1073/pnas.0505408102. Epub 2005 Aug 10.
Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn(2+) in CA1 neurons just before the onset of histologically detectable cell death. Here we show that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca(2+)/Zn(2+)-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn(2+) and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn(2+) in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn(2+) and death of CA1 neurons, although a direct action at the time of the rise in Zn(2+) is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans.
在动物实验中诱导的短暂性全脑或前脑缺血可导致海马CA1锥体神经元选择性、延迟性神经元死亡。一个显著特征是在组织学上可检测到的细胞死亡开始前，CA1神经元细胞内游离锌离子（Zn(2+)）延迟升高。我们在此表明，在缺血后海马中，从Schaffer侧支到CA1突触的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体（AMPARs）在锌离子升高和细胞死亡之前表现出钙（Ca(2+)/锌离子（Zn(2+)）通透、缺乏谷氨酸受体2（GluR2）的AMPARs的特性。缺血后42小时，AMPA兴奋性突触后电流表现出明显的内向整流以及对1-萘基乙酰精胺（Naspm）的显著敏感性，Naspm是一种缺乏GluR2的AMPARs的选择性通道阻滞剂。在对照海马中，AMPA兴奋性突触后电流呈电线性且对Naspm相对不敏感。在损伤后9 - 40小时海马内注射Naspm可显著降低缺血后CA1神经元细胞内游离锌离子（Zn(2+)）的后期升高，并对缺血诱导的细胞死亡提供部分保护。这些结果表明，缺乏GluR2的AMPA受体与缺血诱导的游离锌离子（Zn(2+)）升高及CA1神经元死亡有关，尽管在锌离子（Zn(2+)）升高时的直接作用尚未得到证实。这种受体亚型似乎是干预人类缺血诱导的神经元死亡的一个重要治疗靶点。
