title: Presynaptic NMDA receptor mechanisms for enhancing spontaneous neurotransmitter release.
abstract: NMDA receptors (NMDARs) are required for experience-driven plasticity during formative periods of brain development and are critical for neurotransmission throughout postnatal life. Most NMDAR functions have been ascribed to postsynaptic sites of action, but there is now an appreciation that presynaptic NMDARs (preNMDARs) can modulate neurotransmitter release in many brain regions, including the neocortex. Despite these advances, the cellular mechanisms by which preNMDARs can affect neurotransmitter release are largely unknown. Here we interrogated preNMDAR functions pharmacologically to determine how these receptors promote spontaneous neurotransmitter release in mouse primary visual cortex. Our results provide three new insights into the mechanisms by which preNMDARs can function. First, preNMDARs can enhance spontaneous neurotransmitter release tonically with minimal extracellular Ca(2+) or with major sources of intracellular Ca(2+) blocked. Second, lowering extracellular Na(+) levels reduces the contribution of preNMDARs to spontaneous transmitter release significantly. Third, preNMDAR enhance transmitter release in part through protein kinase C signaling. These data demonstrate that preNMDARs can act through novel pathways to promote neurotransmitter release in the absence of action potentials.
authors: Department of Cell Biology and Physiology, Carolina Institute for Developmental Disabilities, Neuroscience Center, and Curriculum in Neurobiology, University of North Carolina, Chapel Hill, North Carolina, 27599-7545, USA.
authors: Portia A
authors: PA
authors: Kunz
authors: Adam C
authors: AC
authors: Roberts
authors: Benjamin D
authors: BD
authors: Philpot
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D012965:Sodium Chloride / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; C082246:ICI D2788; D013779:Tetrodotoxin; D012965:Sodium Chloride; D015763:2-Amino-5-phosphonovalerate; D002118:Calcium
references: J Neurosci. 1994 Sep;14(9):5202-22
references: 8083731
references: J Neurosci. 2001 Feb 15;21(4):1228-37
references: 11160393
references: Neuron. 2012 Aug 9;75(3):451-66
references: 22884329
references: Neuron. 2008 Oct 23;60(2):298-307
references: 18957221
references: Prog Neurobiol. 2007 Apr;81(5-6):272-93
references: 17188796
references: J Neurosci. 2006 Apr 19;26(16):4166-77
references: 16624937
references: J Neurosci. 2008 Feb 27;28(9):2199-211
references: 18305253
references: J Neurosci. 1999 Jan 1;19(1):193-205
references: 9870950
references: Nat Neurosci. 2002 Nov;5 Suppl:1039-42
references: 12403981
references: Neuroscientist. 2005 Jun;11(3):206-16
references: 15911870
references: Brain Res Mol Brain Res. 2002 Apr 30;100(1-2):43-52
references: 12008020
references: Nat Neurosci. 2011 Mar;14(3):338-44
references: 21297630
references: Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):365-84
references: 16773445
references: J Neurosci. 2007 Sep 12;27(37):9835-45
references: 17855598
references: Brain Res. 1998 Jan 26;782(1-2):240-7
references: 9519269
references: Neuron. 2010 Dec 22;68(6):1109-27
references: 21172613
references: J Alzheimers Dis. 2004 Dec;6(6 Suppl):S61-74
references: 15665416
references: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16661-6
references: 20817852
references: Schizophr Res. 2004 Dec 1;71(2-3):361-70
references: 15474907
references: Nat Neurosci. 2011 Apr;14(4):478-86
references: 21358644
references: Neuropharmacology. 2011 May;60(6):930-6
references: 21281652
references: Neuroscience. 1996 Nov;75(2):339-44
references: 8931000
references: Neurosignals. 2004 Jul-Aug;13(4):175-89
references: 15148446
references: Nature. 1998 Feb 26;391(6670):892-6
references: 9495341
references: Curr Opin Neurobiol. 2005 Jun;15(3):275-81
references: 15919193
references: J Gen Physiol. 1989 Nov;94(5):789-812
references: 2556494
references: J Neurosci. 2005 Mar 2;25(9):2285-94
references: 15745954
references: Curr Opin Neurobiol. 2001 Jun;11(3):327-35
references: 11399431
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14017-21
references: 11717460
references: J Neurol Sci. 2001 Jan 1;182(2):151-9
references: 11137521
references: J Neurophysiol. 2001 Oct;86(4):1644-51
references: 11600627
references: Pharmacol Ther. 2005 Jan;105(1):69-84
references: 15626456
references: Neuron. 2003 Aug 14;39(4):641-54
references: 12925278
references: Neuroscience. 1999;93(3):985-93
references: 10473263
references: Biophys J. 1997 Jul;73(1):220-9
references: 9199786
references: J Physiol. 2002 Dec 1;545(2):521-35
references: 12456831
references: Neuroscientist. 2008 Dec;14(6):609-25
references: 19029059
references: J Neurophysiol. 2008 Jan;99(1):122-32
references: 18003876
references: Nature. 1998 May 28;393(6683):377-81
references: 9620802
references: Nature. 2011 Jun 15;475(7354):91-5
references: 21677641
references: J Physiol. 1990 Mar;422:203-25
references: 1972190
references: Front Synaptic Neurosci. 2010 Jun 17;2:18
references: 21423504
references: J Neurosci. 2009 Sep 16;29(37):11441-50
references: 19759293
references: J Neurosci. 2002 Jul 15;22(14):5823-32
references: 12122044
references: Brain Res. 1999 Jan 23;816(2):609-17
references: 9878886
references: J Neurophysiol. 2002 Apr;87(4):2052-63
references: 11929923
references: PLoS One. 2012;7(6):e39983
references: 22761940
references: Nat Rev Neurosci. 2007 Jun;8(6):413-26
references: 17514195