title: Tonic activation of group I mGluRs modulates inhibitory synaptic strength by regulating KCC2 activity.
abstract: The furosemide-sensitive potassium-chloride cotransporter (KCC2) plays an important role in establishing the intracellular chloride concentration in many neurons within the central nervous system. Consequently, modulation of KCC2 function will regulate the reversal potential for synaptic GABAergic inputs, thus setting the strength of inhibitory transmission. We show that tonic activation of group I metabotropic glutamate receptors (mGluR1s) regulates inhibitory synaptic strength via modulation of KCC2 function in pyramidal neurons of the hippocampal CA3 area. Specifically, group I mGluRs signal via activation of a protein kinase C-dependent pathway to alter KCC2 activity, thereby altering the intracellular chloride concentration, and thus inhibitory synaptic input. This interaction between the glutamatergic and chloride transport systems highlights a novel homeostatic mechanism whereby ambient glutamate levels directly regulate the inhibitory synaptic tone by setting the activity level of KCC2. Thus, mGluRs are poised to play a pivotal role in providing a direct interplay between the excitatory and inhibitory systems in the hippocampus.
authors.affiliation: Johnson and Johnson PRD, 3210 Merryfield Row, San Diego, CA 92121, USA. tbanke@prdus.jnj.com
authors.forename: Tue G
authors.initials: TG
authors.lastname: Banke
authors.forename: Georgi
authors.initials: G
authors.lastname: Gegelashvili
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000502:physiology*; D051379:Mice; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D018094:Receptors, Metabotropic Glutamate; D027981:Symporters; D000096922:K Cl- Cotransporters; C104077:metabotropic glutamate receptor type 1
references.citation: J Neurosci. 1996 Jan 15;16(2):586-94
references.pmid: 8551342
references.citation: J Neurosci. 1997 Oct 1;17(19):7503-22
references.pmid: 9295396
references.citation: Epilepsy Curr. 2002 Mar;2(2):35-38
references.pmid: 15309160
references.citation: J Neurosci. 2001 Aug 15;21(16):5925-34
references.pmid: 11487615
references.citation: Nat Rev Neurosci. 2002 Sep;3(9):728-39
references.pmid: 12209121
references.citation: Brain Res Brain Res Rev. 1999 Jan;29(1):83-120
references.pmid: 9974152
references.citation: Neuropharmacology. 1995 Jan;34(1):1-26
references.pmid: 7623957
references.citation: J Neurosci. 1995 Jun;15(6):4395-407
references.pmid: 7790916
references.citation: Eur J Neurosci. 2003 Dec;18(12):3199-206
references.pmid: 14686894
references.citation: Trends Neurosci. 2003 Apr;26(4):199-206
references.pmid: 12689771
references.citation: J Neurosci. 2006 Nov 8;26(45):11720-5
references.pmid: 17093093
references.citation: J Neurophysiol. 1995 Jul;74(1):122-9
references.pmid: 7472317
references.citation: Nature. 2003 Aug 21;424(6951):938-42
references.pmid: 12931188
references.citation: J Physiol. 2007 Jan 1;578(Pt 1):193-211
references.pmid: 17008374
references.citation: Science. 1995 Aug 18;269(5226):977-81
references.pmid: 7638623
references.citation: Science. 1992 Oct 23;258(5082):597-603
references.pmid: 1329206
references.citation: Brain Res. 1995 Jan 23;670(1):142-6
references.pmid: 7719714
references.citation: J Membr Biol. 2004 Oct 1;201(3):109-37
references.pmid: 15711773
references.citation: J Neurophysiol. 2006 Apr;95(4):2427-38
references.pmid: 16421200
references.citation: J Neurophysiol. 1985 Feb;53(2):557-71
references.pmid: 2984352
references.citation: Neurosci Lett. 1994 Nov 7;181(1-2):78-82
references.pmid: 7898776
references.citation: Brain Res. 2006 Jan 12;1068(1):65-9
references.pmid: 16376311
references.citation: J Neurophysiol. 2002 Oct;88(4):1766-76
references.pmid: 12364505
references.citation: Nat Med. 2005 Nov;11(11):1205-13
references.pmid: 16227993
references.citation: Eur J Neurosci. 2001 Jun;13(12):2205-17
references.pmid: 11454023
references.citation: J Neurophysiol. 1997 Nov;78(5):2287-95
references.pmid: 9356382
references.citation: Neuron. 2003 Aug 28;39(5):807-20
references.pmid: 12948447
references.citation: J Neurosci. 2006 Dec 27;26(52):13443-53
references.pmid: 17192427
references.citation: Eur J Neurosci. 1996 Jul;8(7):1488-500
references.pmid: 8758956
references.citation: Brain Res Mol Brain Res. 1994 Feb;21(3-4):283-92
references.pmid: 8170352
references.citation: Science. 2002 Nov 15;298(5597):1418-21
references.pmid: 12434059
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:12-21
references.pmid: 14684432
references.citation: J Physiol. 1994 Jan 1;474(1):27-33
references.pmid: 8014895
references.citation: J Neurophysiol. 1994 Oct;72(4):1561-9
references.pmid: 7823086
references.citation: J Neurosci. 2004 May 5;24(18):4478-88
references.pmid: 15128862
references.citation: Science. 1986 Jun 13;232(4756):1413-5
references.pmid: 2424084
references.citation: Neuron. 2005 Dec 8;48(5):773-86
references.pmid: 16337915
references.citation: Trends Pharmacol Sci. 1993 Jan;14(1):13-20
references.pmid: 7680175
references.citation: Nature. 1993 May 27;363(6427):347-50
references.pmid: 8388549
references.citation: Science. 2001 Aug 10;293(5532):1159-63
references.pmid: 11498596
references.citation: J Comp Neurol. 1998 Oct 26;400(3):391-407
references.pmid: 9779943
references.citation: Curr Opin Neurobiol. 1999 Jun;9(3):293-8
references.pmid: 10395570
references.citation: Nature. 1990 Oct 25;347(6295):765-7
references.pmid: 2172830
references.citation: J Biol Chem. 2007 Oct 12;282(41):29777-84
references.pmid: 17693402
references.citation: J Physiol. 1995 Jul 1;486 ( Pt 1):163-76
references.pmid: 7562633
references.citation: J Neurophysiol. 1991 Jul;66(1):40-52
references.pmid: 1655995
references.citation: Nature. 1999 Jan 21;397(6716):251-5
references.pmid: 9930699
references.citation: J Neurosci. 2007 Feb 14;27(7):1642-50
references.pmid: 17301172
references.citation: J Neurosci. 1994 Jul;14(7):4433-45
references.pmid: 7517996
references.citation: Neuroscience. 2007 Mar 2;145(1):185-96
references.pmid: 17207578
references.citation: Curr Opin Pharmacol. 2007 Feb;7(1):93-9
references.pmid: 17182282
references.citation: J Physiol. 1995 May 15;485 ( Pt 1):121-34
references.pmid: 7658367
references.citation: Eur J Neurosci. 2008 May;27(10):2515-28
references.pmid: 18547241