Sun Hong-Shuo, Jackson Michael F, Martin Loren J, Jansen Karen, Teves Lucy, Cui Hong, Kiyonaka Shigeki, Mori Yasuo, Jones Michael, Forder Joan P, Golde Todd E, Orser Beverley A, Macdonald John F, Tymianski Michael
Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
Nat Neurosci. 2009 Oct;12(10):1300-7. doi: 10.1038/nn.2395. Epub 2009 Sep 6.
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.
心脏骤停受害者可能会经历短暂的脑灌注不足，导致海马CA1神经元延迟死亡和认知障碍。我们通过抑制瞬时受体电位褪黑素7（TRPM7）的表达来防止成年大鼠出现这种情况。TRPM7是一种瞬时受体电位通道，对胚胎发育至关重要，在体外对细胞存活和微量离子稳态是必需的，并且其在小鼠中的整体缺失是致命的。通过海马内注射携带针对TRPM7的短发夹RNA（shRNA）的病毒载体，在CA1神经元中抑制TRPM7。这对动物存活、神经元和树突形态、神经元兴奋性或突触可塑性没有不良影响，强劲的长时程增强（LTP）就是例证。然而，TRPM7抑制使神经元在脑缺血后对缺血性死亡具有抗性，并保留了神经元形态和功能。此外，它还预防了缺血诱导的LTP缺陷，并保留了恐惧相关和空间导航记忆任务中的表现。因此，TRPM7的区域抑制是可行的，耐受性良好，并能在体内抑制延迟性神经元死亡。
