Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia.
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.
Sun
Hong-Shuo
HS
Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
Jackson
Michael F
MF
Martin
Loren J
LJ
Jansen
Karen
K
Teves
Lucy
L
Cui
Hong
H
Kiyonaka
Shigeki
S
Mori
Yasuo
Y
Jones
Michael
M
Forder
Joan P
JP
Golde
Todd E
TE
Orser
Beverley A
BA
Macdonald
John F
JF
Tymianski
Michael
M
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005239:Fear; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008845:Microinjections / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D050053:TRPM Cation Channels / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D049452:Green Fluorescent Proteins; C486584:Trpm7 protein, rat