title: Glutamate spillover promotes the generation of NMDA spikes.
abstract: NMDA spikes are prominent in the basal dendrites of cortical pyramidal neurons and greatly expand their ability to integrate synaptic inputs. Calcium (Ca) signals during these spikes are important for synaptic plasticity and fundamentally depend on activation of NMDA receptors. However, the factors that shape the activation of these receptors and the initiation of NMDA spikes remain unclear. Here we examine the properties of NMDA spikes in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon imaging, we demonstrate that NMDA spikes evoke large Ca signals in both postsynaptic spines and nearby dendrites. We find that the dendrite Ca signals depend on NMDA and AMPA receptors but not sodium (Na) or Ca channels. Using voltage-clamp recordings, we show that activation of dendrite NMDA receptors is enhanced by concerted synaptic activity. Blocking glutamate reuptake further increases activation of these receptors and promotes the initiation of NMDA spikes. We conclude that glutamate spillover and recruitment of extrasynaptic receptors contribute to the initiation of NMDA spikes. These results have important implications for how synaptic activity generates both electrical and biochemical signals in dendrites and spines.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Chalifoux
authors.forename: Adam G
authors.initials: AG
authors.lastname: Carter
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000494:pharmacology; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000166:cytology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D018709:Statistics, Nonparametric
chemical_list: D002121:Calcium Channel Blockers; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D011810:Quinoxalines; C120673:benzyloxyaspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D001224:Aspartic Acid; D018698:Glutamic Acid; D004533:Egtazic Acid; D016202:N-Methylaspartate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium; C000543:cyclopiazonic acid
references.citation: Nat Neurosci. 2002 Jul;5(7):657-64
references.pmid: 12055631
references.citation: J Neurosci. 2007 Aug 15;27(33):8967-77
references.pmid: 17699678
references.citation: Neuron. 1998 Nov;21(5):1189-200
references.pmid: 9856473
references.citation: Neuron. 2002 Jan 31;33(3):439-52
references.pmid: 11832230
references.citation: Nature. 1996 May 2;381(6577):71-5
references.pmid: 8609991
references.citation: Neuron. 1996 Sep;17(3):461-74
references.pmid: 8816709
references.citation: Nature. 2000 Mar 16;404(6775):285-9
references.pmid: 10749211
references.citation: J Physiol. 2004 Oct 1;560(Pt 1):27-36
references.pmid: 15319420
references.citation: Neuron. 2010 Apr 15;66(1):101-13
references.pmid: 20399732
references.citation: Nature. 2002 Jul 18;418(6895):326-31
references.pmid: 12124625
references.citation: J Neurosci. 1999 May 15;19(10):4180-8
references.pmid: 10234045
references.citation: PLoS Biol. 2009 Sep;7(9):e1000190
references.pmid: 19753104
references.citation: J Neurosci. 2005 Apr 13;25(15):3940-51
references.pmid: 15829646
references.citation: Curr Opin Neurobiol. 1999 Jun;9(3):305-13
references.pmid: 10395573
references.citation: Science. 2001 Sep 21;293(5538):2272-5
references.pmid: 11567143
references.citation: J Physiol. 2008 Mar 15;586(6):1519-27
references.pmid: 18202095
references.citation: J Neurosci. 2006 Jul 12;26(28):7424-32
references.pmid: 16837590
references.citation: Neuron. 2007 Jan 18;53(2):249-60
references.pmid: 17224406
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9596-601
references.pmid: 9689126
references.citation: J Neurosci. 1997 Jan 1;17(1):190-203
references.pmid: 8987748
references.citation: Neuron. 1998 Sep;21(3):561-70
references.pmid: 9768842
references.citation: Neuron. 1999 Jun;23(2):377-84
references.pmid: 10399942
references.citation: Neuron. 2007 Dec 6;56(5):866-79
references.pmid: 18054862
references.citation: Neuron. 2006 Apr 20;50(2):291-307
references.pmid: 16630839
references.citation: J Neurosci. 2008 Dec 10;28(50):13457-66
references.pmid: 19074019
references.citation: Neuron. 1997 Feb;18(2):281-93
references.pmid: 9052798
references.citation: J Physiol. 1997 Dec 15;505 ( Pt 3):617-32
references.pmid: 9457640
references.citation: J Neurosci. 2009 Sep 23;29(38):11891-903
references.pmid: 19776275
references.citation: J Neurophysiol. 2008 May;99(5):2584-601
references.pmid: 18337370
references.citation: J Neurosci. 2000 Jun 15;20(12):4423-34
references.pmid: 10844011
references.citation: Nat Neurosci. 2004 Jun;7(6):621-7
references.pmid: 15156147
references.citation: Biophys J. 2000 May;78(5):2655-67
references.pmid: 10777761
references.citation: Nat Neurosci. 2007 Feb;10(2):206-14
references.pmid: 17206140
references.citation: J Neurosci. 2000 Mar 1;20(5):1791-9
references.pmid: 10684880
references.citation: J Physiol. 2007 Dec 1;585(Pt 2):447-68
references.pmid: 17932150
references.citation: J Neurosci. 2006 Dec 6;26(49):12717-26
references.pmid: 17151275
references.citation: Trends Neurosci. 1997 Sep;20(9):377-84
references.pmid: 9292962
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12347-52
references.pmid: 17640908
references.citation: J Neurosci. 1999 Mar 15;19(6):1976-87
references.pmid: 10066251
references.citation: Neuron. 1999 Jan;22(1):115-24
references.pmid: 10027294
references.citation: J Neurophysiol. 2009 Mar;101(3):1524-41
references.pmid: 19118105
references.citation: J Neurosci. 1998 May 1;18(9):3158-70
references.pmid: 9547224
references.citation: Nat Neurosci. 2002 Apr;5(4):325-31
references.pmid: 11896395
references.citation: J Neurosci. 2006 Jun 21;26(25):6704-15
references.pmid: 16793878
references.citation: J Neurosci. 2005 Jun 29;25(26):6037-46
references.pmid: 15987933
references.citation: Curr Opin Neurobiol. 2001 Jun;11(3):343-8
references.pmid: 11399433
references.citation: J Neurosci. 2000 Mar 1;20(5):2054-63
references.pmid: 10684906
references.citation: J Neurosci. 2011 Mar 16;31(11):4221-32
references.pmid: 21411663
references.citation: J Physiol. 1997 Dec 15;505 ( Pt 3):605-16
references.pmid: 9457639
references.citation: Neuron. 2004 Oct 28;44(3):483-93
references.pmid: 15504328
references.citation: Nat Neurosci. 2010 Aug;13(8):958-66
references.pmid: 20601948
references.citation: Annu Rev Neurosci. 2005;28:503-32
references.pmid: 16033324