Suppression of Hippocampal TRPM7 Protein Prevents Delayed Neuronal Death in Brain Ischemia

Overview

Journal Nat Neurosci

Date 2009 Sep 8

PMID 19734892

Citations 150

Authors

Hong-Shuo Sun

Michael F Jackson

Loren J Martin

Karen Jansen

Lucy Teves

Hong Cui

Shigeki Kiyonaka

Yasuo Mori

Michael Jones

Joan P Forder

Todd E Golde

Beverley A Orser

John F Macdonald

Michael Tymianski

Affiliations

Soon will be listed here.

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.

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References

Jin J, Desai B, Navarro B, Donovan A, Andrews N, Clapham D . Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science. 2008; 322(5902):756-60. PMC: 2605283. DOI: 10.1126/science.1163493. View

Lisman J, Schulman H, Cline H . The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002; 3(3):175-90. DOI: 10.1038/nrn753. View

Kumar R, Azam S, Sullivan J, Owen C, Cavener D, Zhang P . Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem. 2001; 77(5):1418-21. DOI: 10.1046/j.1471-4159.2001.00387.x. View

Morris R . Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984; 11(1):47-60. DOI: 10.1016/0165-0270(84)90007-4. View

Nadler M, Hermosura M, Inabe K, Perraud A, Zhu Q, Stokes A . LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature. 2001; 411(6837):590-5. DOI: 10.1038/35079092. View

Schmitz C, Dorovkov M, Zhao X, Davenport B, Ryazanov A, Perraud A . The channel kinases TRPM6 and TRPM7 are functionally nonredundant. J Biol Chem. 2005; 280(45):37763-71. DOI: 10.1074/jbc.M509175200. View

Morris G, Bullock R, MARSHALL S, Marmarou A, Maas A, Marshall L . Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators. J Neurosurg. 1999; 91(5):737-43. DOI: 10.3171/jns.1999.91.5.0737. View

Volpe B, Pulsinelli W, Tribuna J, DAVIS H . Behavioral performance of rats following transient forebrain ischemia. Stroke. 1984; 15(3):558-62. DOI: 10.1161/01.str.15.3.558. View

Wei W, Sun H, Olah M, Sun X, Czerwinska E, Czerwinski W . TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations. Proc Natl Acad Sci U S A. 2007; 104(41):16323-8. PMC: 2042205. DOI: 10.1073/pnas.0701149104. View

10.

Schmitz C, Perraud A, Johnson C, Inabe K, Smith M, Penner R . Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell. 2003; 114(2):191-200. DOI: 10.1016/s0092-8674(03)00556-7. View

11.

Pulsinelli W, BRIERLEY J . A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979; 10(3):267-72. DOI: 10.1161/01.str.10.3.267. View

12.

Corish P, Tyler-Smith C . Attenuation of green fluorescent protein half-life in mammalian cells. Protein Eng. 1999; 12(12):1035-40. DOI: 10.1093/protein/12.12.1035. View

13.

Gavrieli Y, Sherman Y, Ben-Sasson S . Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992; 119(3):493-501. PMC: 2289665. DOI: 10.1083/jcb.119.3.493. View

14.

Kaneko S, Kawakami S, Hara Y, Wakamori M, Itoh E, Minami T . A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J Pharmacol Sci. 2006; 101(1):66-76. DOI: 10.1254/jphs.fp0060128. View

15.

Mullen R, Buck C, Smith A . NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992; 116(1):201-11. DOI: 10.1242/dev.116.1.201. View

16.

Sun H, Feng Z, Miki T, Seino S, French R . Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol. 2005; 95(4):2590-601. DOI: 10.1152/jn.00970.2005. View

17.

Whitlock J, Heynen A, Shuler M, Bear M . Learning induces long-term potentiation in the hippocampus. Science. 2006; 313(5790):1093-7. DOI: 10.1126/science.1128134. View

18.

Lawlor P, Bland R, Das P, Price R, Holloway V, Smithson L . Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Abeta levels. Mol Neurodegener. 2007; 2:11. PMC: 1906777. DOI: 10.1186/1750-1326-2-11. View

19.

Fanselow M . Conditioned and unconditional components of post-shock freezing. Pavlov J Biol Sci. 1980; 15(4):177-82. DOI: 10.1007/BF03001163. View

20.

Block F . Global ischemia and behavioural deficits. Prog Neurobiol. 1999; 58(3):279-95. DOI: 10.1016/s0301-0082(98)00085-9. View