Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia
Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia
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DOI：
10.1038/nn.2395
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发表时间：
2009-10-01
影响因子：
25
通讯作者：
Tymianski, Michael
中科院分区：
文献类型：
--
作者：
Sun, Hong-Shuo;Jackson, Michael F.;Tymianski, Michael
心脏骤停患者可能会经历一过性脑低灌流，导致海马CA1区神经元延迟死亡和认知障碍。我们在成年大鼠中通过抑制瞬时受体电位Melastatin 7(TRPM7)的表达来防止这种情况的发生，TRPM7是一种瞬时受体电位通道，对于胚胎发育是必不可少的，对于细胞存活和体外痕量离子动态平衡是必要的，而且它在小鼠中的全局缺失是致命的。通过海马区注射携带TRPM7特异性shRNA的病毒载体，抑制了CA1神经元中的TRPM7。这对动物的存活、神经元和树突的形态、神经元的兴奋性或突触的可塑性没有不良影响，如强健的长时程增强(LTP)所示。然而，抑制TRPM7使神经元抵抗脑缺血后的缺血性死亡，并保留了神经元的形态和功能。此外，它还防止了缺血导致的LTP缺陷，并在与恐惧相关的和空间导航记忆任务中保持了表现。因此，局部抑制TRPM7是可行的，耐受性良好，并可抑制体内迟发性神经元死亡。
Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-associated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.