Glutamate and ATP signalling in white matter pathology.
Excessive signalling by excitatory neurotransmitters like glutamate and ATP can be deleterious to neurons and oligodendroglia, and cause disease. In particular, sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA) receptors damages oligodendrocytes, a feature that depends entirely on Ca(2+) overload of the cytoplasm and that can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake by activated microglia can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity. Moreover, non-lethal, brief activation of kainate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack as a consequence of oxidative stress. In addition to glutamate, ATP signalling can directly trigger oligodendrocyte excitotoxicity via activation of Ca(2+) -permeable P2X7 purinergic receptors, which mediates ischaemic damage to white matter (WM) and causes lesions that are reminiscent of multiple sclerosis (MS) plaques. Conversely, blockade of P2X7 receptors attenuates post-ischaemic injury to WM and ameliorates chronic experimental autoimmune encephalomyelitis, a model of MS. Importantly, P2X7 expression is elevated in normal-appearing WM in patients with MS, suggesting that signalling through this receptor in oligodendrocytes may be enhanced in this disease. Altogether, these observations reveal novel mechanisms by which altered glutamate and ATP homeostasis can trigger oligodendrocyte death. This review aims at summarizing current knowledge about the mechanisms leading to WM damage as a consequence of altered neurotransmitter signalling, and their relevance to disease. This knowledge will generate new therapeutic avenues to treat more efficiently acute and chronic WM pathology.
Departamento de Neurociencias and CIBERNED, Universidad del País Vasco, Leioa, Vizcaya, Spain Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Spain. carlos.matute@ehu.es
Carlos
C
Matute
D000255:Adenosine Triphosphate / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009836:Oligodendroglia / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018698:Glutamic Acid; D000255:Adenosine Triphosphate
J Physiol. 1995 Feb 15;483 ( Pt 1):41-57
7776240
J Neurosci. 2001 Mar 15;21(6):1975-82
11245682
Ann Neurol. 2004 Apr;55(4):458-68
15048884
Recent Pat CNS Drug Discov. 2010 Jan;5(1):35-45
19705995
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10229-34
9707629
Neurochem Int. 2010 Nov;57(4):359-66
20380859
J Cereb Blood Flow Metab. 2002 Sep;22(9):1090-7
12218414
Nat Med. 2000 Jan;6(1):62-6
10613825
Stroke. 2000 Jul;31(7):1709-14
10884477
Semin Perinatol. 2004 Dec;28(6):405-14
15693397
Lancet Neurol. 2009 Jan;8(1):110-24
19081519
Brain. 2004 Jun;127(Pt 6):1313-31
15130951
Cell Calcium. 2010 Feb;47(2):150-7
20036774
Glia. 2006 Jan 15;53(2):212-24
16206168
Cerebrovasc Dis. 2002;13 Suppl 2:53-7
11901244
J Cereb Blood Flow Metab. 2004 Apr;24(4):392-8
15087708
Neuron. 1996 Mar;16(3):675-86
8785064
Eur J Pharmacol. 2002 Jul 5;447(2-3):247-60
12151016
J Anat. 2007 Jun;210(6):693-702
17504270
Curr Drug Targets CNS Neurol Disord. 2003 Dec;2(6):403-12
14683468
Neuroscientist. 2007 Feb;13(1):28-37
17229973
Stroke. 2003 Feb;34(2):330-2
12574526
J Comp Neurol. 2006 Jul 1;497(1):61-77
16680761
Ann Neurol. 2009 Feb;65(2):160-6
19224531
J Neurosci. 2007 Aug 29;27(35):9525-33
17728465
Nat Rev Neurosci. 2005 Aug;6(8):626-40
16025096
Nat Rev Drug Discov. 2005 Feb;4(2):131-44
15665858
J Immunol. 2007 May 15;178(10):6549-56
17475885
Pharmacol Rev. 1999 Mar;51(1):7-61
10049997
Glia. 2004 Nov 15;48(3):185-96
15390115
J Cereb Blood Flow Metab. 2003 Mar;23(3):381-4
12621313
Eur J Neurosci. 1999 Jul;11(7):2226-36
10383611
Trends Mol Med. 2006 Jul;12(7):289-92
16750425
FASEB J. 2010 Feb;24(2):337-45
19812374
Nature. 2005 Dec 22;438(7071):1167-71
16372012
Neuroscientist. 2009 Apr;15(2):126-33
19307420
Clin Neuropharmacol. 2001 Sep-Oct;24(5):254-64
11586110
J Neurosci. 2008 Feb 6;28(6):1479-89
18256269
Glia. 2009 Feb;57(3):307-19
18942747
J Neurosci. 2000 Jan 1;20(1):34-42
10627578
Neurobiol Dis. 2006 Jan;21(1):154-64
16061389
Glia. 2005 Oct;52(1):36-46
15892126
Glia. 2009 Aug 15;57(11):1168-77
19170183
Mol Neurobiol. 2009 Jun;39(3):190-208
19283516
Brain. 2010 Sep;133(9):2603-11
20802204
Nat Med. 2004 Aug;10(8):821-7
15258577
J Neuroimmunol. 2008 Mar;195(1-2):194-8
18378006
J Neurosci. 2004 May 5;24(18):4412-20
15128855
Trends Neurosci. 2001 Apr;24(4):224-30
11250007
J Neurosci. 2000 Feb 1;20(3):1190-8
10648723
Stroke. 1996 Sep;27(9):1641-6; discussion 1647
8784142
Ann Neurol. 2009 Feb;65(2):151-9
19224535
Prog Neurobiol. 2006 Apr;78(6):327-46
16697102
Physiol Rev. 1998 Jan;78(1):99-141
9457170
Glia. 2010 Apr 15;58(6):730-40
20029962
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7751-6
15136737
Nat Neurosci. 2007 Mar;10(3):311-20
17293860
Ann Neurol. 2009 Nov;66(5):682-93
19938170
Neurology. 2003 Oct 28;61(8):1113-20
14581674
Curr Opin Neurobiol. 2004 Jun;14(3):346-52
15194115
J Physiol. 2006 Nov 15;577(Pt 1):191-204
16945971
Brain. 2005 May;128(Pt 5):1016-25
15758036
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5621-6
10792049
J Neurosci. 1999 Jul 15;19(14):RC16
10407058
Nature. 2006 Feb 23;439(7079):988-92
16372019
Nat Rev Neurosci. 2006 Jun;7(6):423-36
16715052
Nat Neurosci. 2005 Jun;8(6):752-8
15895084
J Neurosci. 2003 Oct 22;23(29):9519-28
14573531
Pflugers Arch. 2006 Aug;452(5):615-21
16791619
Nature. 2005 Dec 22;438(7071):1162-6
16372011
J Immunol. 2006 Mar 1;176(5):3115-26
16493071
J Neurotrauma. 2004 Jun;21(6):754-74
15253803
J Neuroinflammation. 2008 Aug 08;5:33
18691411
Neuroscience. 2008 Jun 2;153(4):1034-47
18423997
Nat Med. 2000 Jan;6(1):67-70
10613826
Neuron. 2003 Jun 5;38(5):685-8
12797954
Arch Neurol. 2009 Aug;66(8):972-8
19667218
Sci STKE. 2004 Oct 19;2004(255):re16
15494561
Glia. 2006 Nov 15;54(7):666-75
17006895
J Neurosci. 2001 Jun 15;21(12):4237-48
11404409
Brain Res. 2003 Nov 21;991(1-2):104-12
14575882
J Neurosci. 2006 Mar 22;26(12):3220-8
16554473
Curr Mol Med. 2004 Mar;4(2):113-30
15032708
Ann Neurol. 2001 Aug;50(2):169-80
11506399
Science. 2005 May 27;308(5726):1314-8
15831717
J Neurosci. 2009 Mar 25;29(12):3781-91
19321774
J Neurotrauma. 2006 Mar-Apr;23(3-4):318-34
16629619
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12489-93
19666625
Pediatr Res. 2008 Jun;63(6):656-61
18520330
J Neurol Sci. 2005 Jun 15;233(1-2):3-13
15899499
Nat Neurosci. 2006 Dec;9(12):1512-9
17115040
Prog Neurobiol. 2001 Sep;65(1):1-105
11369436
Nat Neurosci. 2007 Mar;10(3):321-30
17293857
J Neurosci. 2008 Jun 25;28(26):6670-8
18579741
Neuroscience. 2009 Jan 12;158(1):266-74
18314276