title: Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus.
abstract: Microglia are highly dynamic immune cells of the CNS and their dynamism is proposed to be regulated by neuronal activities. However, the mechanisms underlying neuronal regulation of microglial dynamism have not been determined. Here, we found an increased number of microglial primary processes in the hippocampus during KA-induced seizure activity. Consistently, global glutamate induced robust microglial process extension toward neurons in both brain slices and in the intact brain in vivo. The mechanism of the glutamate-induced microglial process extension involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and microglial response through P2Y12 receptors. Seizure-induced increases in microglial process numbers were also dependent on NMDA receptor activation. Finally, we found that P2Y12 KO mice exhibited reduced seizure-induced increases in microglial process numbers and worsened KA-induced seizure behaviors. Our results elucidate the molecular mechanisms underlying microglia-neuron communication that may be potentially neuroprotective in the epileptic brain.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Ukpong B
authors.initials: UB
authors.lastname: Eyo
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Swiatkowski
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Aparna
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Ashley
authors.initials: A
authors.lastname: Bispo
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854 lwu@dls.rutgers.edu.
authors.forename: Long-Jun
authors.initials: LJ
authors.lastname: Wu
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D022081:Cell Surface Extensions / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013226:Status Epilepticus / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D018683:Excitatory Amino Acid Agents; D008164:Luminescent Proteins; C548577:P2ry12 protein, mouse; D019707:Receptors, Chemokine; D016194:Receptors, N-Methyl-D-Aspartate; D058925:Receptors, Purinergic P2Y12; D026941:Sodium Channel Blockers; D011189:Potassium Chloride
keywords: NMDA receptor; P2Y12 receptor; epilepsy; glutamate; microglia; process extension
references.citation: Science. 2011 Sep 9;333(6048):1456-8
references.pmid: 21778362
references.citation: Ann Neurol. 2005 Feb;57(2):226-35
references.pmid: 15668975
references.citation: Ann Neurol. 2012 Oct;72(4):536-49
references.pmid: 23109148
references.citation: Annu Rev Immunol. 2009;27:119-45
references.pmid: 19302036
references.citation: Dev Cell. 2012 Jun 12;22(6):1138-48
references.pmid: 22632801
references.citation: J Neurosci. 2009 Apr 1;29(13):3974-80
references.pmid: 19339593
references.citation: Glia. 2013 Dec;61(12):2023-37
references.pmid: 24123492
references.citation: Glia. 2007 Jun;55(8):810-21
references.pmid: 17357150
references.citation: Neurosci Lett. 1995 May 19;191(1-2):27-30
references.pmid: 7659283
references.citation: Neural Plast. 2013;2013:456857
references.pmid: 24078884
references.citation: Mol Cell Biol. 2000 Jun;20(11):4106-14
references.pmid: 10805752
references.citation: Glia. 2010 Jul;58(9):1133-44
references.pmid: 20468054
references.citation: PLoS One. 2013 Oct 23;8(10):e77722
references.pmid: 24194896
references.citation: Nat Neurosci. 2013 May;16(5):543-51
references.pmid: 23525041
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6436-41
references.pmid: 17389364
references.citation: Science. 2008 Dec 5;322(5907):1555-9
references.pmid: 19056988
references.citation: Eur J Neurosci. 2009 Mar;29(6):1108-18
references.pmid: 19302147
references.citation: Nat Rev Neurol. 2011 Jan;7(1):31-40
references.pmid: 21135885
references.citation: J Neurocytol. 2002 Sep-Nov;31(8-9):681-92
references.pmid: 14501207
references.citation: J Neurosci. 2008 Mar 12;28(11):2892-902
references.pmid: 18337420
references.citation: Epilepsia. 2008;49 Suppl 2:33-41
references.pmid: 18226170
references.citation: Proc Natl Acad Sci U S A. 2008 May 27;105(21):7588-93
references.pmid: 18508976
references.citation: Dev Cell. 2012 Dec 11;23(6):1189-202
references.pmid: 23201120
references.citation: Eur J Neurosci. 2000 Jun;12(6):2049-58
references.pmid: 10886344
references.citation: Glia. 2013 Jan;61(1):24-36
references.pmid: 22829357
references.citation: Nat Neurosci. 2014 Jan;17(1):131-43
references.pmid: 24316888
references.citation: Nat Neurosci. 2012 Mar 04;15(4):565-73
references.pmid: 22388960
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):E197-205
references.pmid: 22167804
references.citation: Neuron. 2004 Feb 19;41(4):535-47
references.pmid: 14980203
references.citation: Epilepsy Res. 2008 Jan;78(1):50-9
references.pmid: 18054462
references.citation: Nat Commun. 2012;3:1227
references.pmid: 23187627
references.citation: J Neurophysiol. 2008 Apr;99(4):2026-32
references.pmid: 18256162
references.citation: Trends Neurosci. 2010 Feb;33(2):93-102
references.pmid: 20022389
references.citation: Lancet. 1993 Jun 26;341(8861):1607-10
references.pmid: 8099987
references.citation: Epilepsia. 2005 Apr;46(4):470-2
references.pmid: 15816939
references.citation: J Neurosci. 2008 Sep 10;28(37):9133-44
references.pmid: 18784294
references.citation: Glia. 2003 Dec;44(3):242-50
references.pmid: 14603465
references.citation: PLoS One. 2011 Jan 25;6(1):e15973
references.pmid: 21283568
references.citation: FEBS Lett. 2006 Jan 9;580(1):239-44
references.pmid: 16364313
references.citation: Nat Rev Neurosci. 2007 Dec;8(12):935-47
references.pmid: 17987031
references.citation: Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
references.pmid: 4110397
references.citation: Glia. 2008 Feb;56(3):331-41
references.pmid: 18098126
references.citation: J Neurochem. 2001 Feb;76(3):892-900
references.pmid: 11158261
references.citation: PLoS Biol. 2010 Nov 02;8(11):e1000527
references.pmid: 21072242
references.citation: Glia. 2012 Nov;60(11):1747-60
references.pmid: 22847985
references.citation: Nat Neurosci. 2005 Jun;8(6):752-8
references.pmid: 15895084
references.citation: J Neuroinflammation. 2012 Jan 31;9:27
references.pmid: 22293457
references.citation: Glia. 2011 Apr;59(4):521-39
references.pmid: 21319220
references.citation: J Neurochem. 2012 Apr;121(2):217-27
references.pmid: 22335470
references.citation: Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4444-51
references.pmid: 19443728
references.citation: J Neurosci. 2008 May 7;28(19):4949-56
references.pmid: 18463248
references.citation: J Neurosci. 2008 Apr 30;28(18):4702-11
references.pmid: 18448647
references.citation: Glia. 2009 Nov 15;57(15):1610-8
references.pmid: 19382211
references.citation: J Neuroimmune Pharmacol. 2013 Jun;8(3):494-509
references.pmid: 23354784
references.citation: Neuron. 2000 Oct;28(1):41-51
references.pmid: 11086982
references.citation: Science. 2005 May 27;308(5726):1314-8
references.pmid: 15831717
references.citation: Nat Neurosci. 2006 Dec;9(12):1512-9
references.pmid: 17115040
references.citation: Neuron. 2012 May 24;74(4):691-705
references.pmid: 22632727