Journal Article

Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia

Jansen, Karen, Kiyonaka, Shigeki, Jackson, Michael F, Tymianski, Michael, Teves, Lucy, Martin, Loren J, Jones, Michael, Mori, Yasuo, Cui, Hong, Orser, Beverley A, Sun, Hong-Shuo, MacDonald, John F, Forder, Joan P, Golde, Todd E

2009

Overview

In a model of stroke, the authors show that suppressing the expression of TRPM7 in hippocampal CA1 neurons conferred resistance to ischemic death, preserving function and morphology. Also, TRPM7 suppression prevented ischemia-induced deficits in LTP and fear-associated and spatial navigational memory tasks. 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 .

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Analysis of Variance / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain Ischemia - pathology / Brain Ischemia - prevention & control / Cell Death - drug effects / Cell Death - genetics / Cells, Cultured / Cerebral ischemia / Disease Models, Animal / Embryonic development / Excitatory Postsynaptic Potentials - drug effects / Excitatory Postsynaptic Potentials - genetics / Fear / Gene Expression Regulation - drug effects / Gene Expression Regulation - physiology / Gene Transfer Techniques / Green Fluorescent Proteins - genetics / Hippocampus - metabolism / Hippocampus - pathology / Humans / In Vitro Techniques / Male / Maze Learning - physiology / Memory - physiology / Mice / Microinjections - methods / Neurobiology / Neurons - drug effects / Neurons - physiology / Neurosciences / Physiological aspects / Prevention / Rats / Rats, Wistar / Risk factors / RNA, Small Interfering - administration & dosage / RNA, Small Interfering - therapeutic use / Transfection - methods / TRPM Cation Channels - metabolism