title: Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia.
abstract: 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.
authors.affiliation: Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: Hong-Shuo
authors.initials: HS
authors.lastname: Sun
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen
authors.forename: Lucy
authors.initials: L
authors.lastname: Teves
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.forename: Joan P
authors.initials: JP
authors.lastname: Forder
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: John F
authors.initials: JF
authors.lastname: Macdonald
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: 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
chemical_list: D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D049452:Green Fluorescent Proteins; C486584:Trpm7 protein, rat