Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Neurosci. 28 (40): 10151-10166

Copyright © 2008 by the Society for Neuroscience.


Spontaneous and Evoked Glutamate Release Activates Two Populations of NMDA Receptors with Limited Overlap

Deniz Atasoy,1 Mert Ertunc,1 Krista L. Moulder,3 Justin Blackwell,4 ChiHye Chung,1 Jianzhong Su,4 , and Ege T. Kavalali1,2

Departments of 1Neuroscience and 2Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, 3Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and 4Department of Mathematics, University of Texas at Arlington, Arlington, Texas 76019-0408

Correspondence should be addressed to Dr. Ege T. Kavalali, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: Ege.Kavalali{at}

Abstract: In a synapse, spontaneous and action-potential-driven neurotransmitter release is assumed to activate the same set of postsynaptic receptors. Here, we tested this assumption using (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801), a well characterized use-dependent blocker of NMDA receptors. NMDA-receptor-mediated spontaneous miniature EPSCs (NMDA-mEPSCs) were substantially decreased by MK-801 within 2 min in a use-dependent manner. In contrast, MK-801 application at rest for 10 min did not significantly impair the subsequent NMDA-receptor-mediated evoked EPSCs (NMDA-eEPSCs). Brief stimulation in the presence of MK-801 significantly depressed evoked NMDA-eEPSCs but only mildly affected the spontaneous NMDA-mEPSCs detected on the same cell. Optical imaging of synaptic vesicle fusion showed that spontaneous and evoked release could occur at the same synapse albeit without correlation between their kinetics. In addition, modeling glutamate diffusion and NMDA receptor activation revealed that postsynaptic densities larger than ~0.2 µm2 can accommodate two populations of NMDA receptors with nonoverlapping responsiveness. Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side.

Key Words: synaptic vesicle release • synaptic transmission • synaptic communication • synapse • NMDA receptor • synaptic plasticity • neurotransmission

Received for publication May 30, 2008. Revision received July 26, 2008. Accepted for publication Aug. 20, 2008.

Correspondence should be addressed to Dr. Ege T. Kavalali, Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: Ege.Kavalali{at}

Innervation by a GABAergic Neuron Depresses Spontaneous Release in Glutamatergic Neurons and Unveils the Clamping Phenotype of Synaptotagmin-1.
K. D. B. Wierda and J. B. Sorensen (2014)
J. Neurosci. 34, 2100-2110
   Abstract »    Full Text »    PDF »
Spontaneous and Evoked Release Are Independently Regulated at Individual Active Zones.
J. E. Melom, Y. Akbergenova, J. P. Gavornik, and J. T. Littleton (2013)
J. Neurosci. 33, 17253-17263
   Abstract »    Full Text »    PDF »
Acute Suppression of Spontaneous Neurotransmission Drives Synaptic Potentiation.
E. Nosyreva, K. Szabla, A. E. Autry, A. G. Ryazanov, L. M. Monteggia, and E. T. Kavalali (2013)
J. Neurosci. 33, 6990-7002
   Abstract »    Full Text »    PDF »
Eye opening and PSD95 are required for long-term potentiation in developing superior colliculus.
J.-P. Zhao, Y. Murata, and M. Constantine-Paton (2013)
PNAS 110, 707-712
   Abstract »    Full Text »    PDF »
The unsilent majority-TRPV1 drives "spontaneous" transmission of unmyelinated primary afferents within cardiorespiratory NTS.
M. C. Andresen, M. E. Hofmann, and J. A. Fawley (2012)
Am J Physiol Regulatory Integrative Comp Physiol 303, R1207-R1216
   Abstract »    Full Text »    PDF »
Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis.
H. Kasai, N. Takahashi, and H. Tokumaru (2012)
Physiol Rev 92, 1915-1964
   Abstract »    Full Text »    PDF »
Enhanced NMDA Receptor-Dependent Thalamic Excitation and Network Oscillations in Stargazer Mice.
C. J. Lacey, A. Bryant, J. Brill, and J. R. Huguenard (2012)
J. Neurosci. 32, 11067-11081
   Abstract »    Full Text »    PDF »
Synaptic Vesicle Pools and Dynamics.
A. A. Alabi and R. W. Tsien (2012)
Cold Spring Harb Perspect Biol 4, a013680
   Abstract »    Full Text »    PDF »
Independent Vesicle Pools Underlie Different Modes of Release during Neuronal Development.
L. C. Andreae, N. Ben Fredj, and J. Burrone (2012)
J. Neurosci. 32, 1867-1874
   Abstract »    Full Text »    PDF »
GABAB-mediated inhibition of multiple modes of glutamate release in the nucleus of the solitary tract.
J. A. Fawley, J. H. Peters, and M. C. Andresen (2011)
J Neurophysiol 106, 1833-1840
   Abstract »    Full Text »    PDF »
Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission.
E. D. Nelson, M. Bal, E. T. Kavalali, and L. M. Monteggia (2011)
J Neurophysiol 106, 193-201
   Abstract »    Full Text »    PDF »
EphA activation overrides the presynaptic actions of BDNF.
C. Bi, X. Yue, R. Zhou, and M. R. Plummer (2011)
J Neurophysiol 105, 2364-2374
   Abstract »    Full Text »    PDF »
Rapid Active Zone Remodeling during Synaptic Plasticity.
A. Weyhersmuller, S. Hallermann, N. Wagner, and J. Eilers (2011)
J. Neurosci. 31, 6041-6052
   Abstract »    Full Text »    PDF »
Use-Dependent AMPA Receptor Block Reveals Segregation of Spontaneous and Evoked Glutamatergic Neurotransmission.
Y. Sara, M. Bal, M. Adachi, L. M. Monteggia, and E. T. Kavalali (2011)
J. Neurosci. 31, 5378-5382
   Abstract »    Full Text »    PDF »
Spontaneous Glutamate Release Is Independent of Calcium Influx and Tonically Activated by the Calcium-Sensing Receptor.
N. P. Vyleta and S. M. Smith (2011)
J. Neurosci. 31, 4593-4606
   Abstract »    Full Text »    PDF »
Depolarization-Induced Suppression of Spontaneous Release in the Avian Midbrain.
M. A. Penzo and J. L. Pena (2011)
J. Neurosci. 31, 3602-3609
   Abstract »    Full Text »    PDF »
Spontaneous Neurotransmission: An Independent Pathway for Neuronal Signaling?.
E. T. Kavalali, C. Chung, M. Khvotchev, J. Leitz, E. Nosyreva, J. Raingo, and D. M. O. Ramirez (2011)
Physiology 26, 45-53
   Abstract »    Full Text »    PDF »
Post-tetanic potentiation is caused by two signalling mechanisms affecting quantal size and quantal content.
L. Xue and L.-G. Wu (2010)
J. Physiol. 588, 4987-4994
   Abstract »    Full Text »    PDF »
Postsynaptic GluA1 enables acute retrograde enhancement of presynaptic function to coordinate adaptation to synaptic inactivity.
M. Lindskog, L. Li, R. D. Groth, D. Poburko, T. C. Thiagarajan, X. Han, and R. W. Tsien (2010)
PNAS 107, 21806-21811
   Abstract »    Full Text »    PDF »
Developmental regulation of protein interacting with C kinase 1 (PICK1) function in hippocampal synaptic plasticity and learning.
L. Volk, C.-H. Kim, K. Takamiya, Y. Yu, and R. L. Huganir (2010)
PNAS 107, 21784-21789
   Abstract »    Full Text »    PDF »
Activity-Dependent Augmentation of Spontaneous Neurotransmission during Endoplasmic Reticulum Stress.
E. Nosyreva and E. T. Kavalali (2010)
J. Neurosci. 30, 7358-7368
   Abstract »    Full Text »    PDF »
Parsing Spontaneous and Evoked Neurotransmission on Both Sides of the Synapse.
P. E. Rothwell (2010)
J. Neurosci. 30, 6480-6481
   Full Text »    PDF »
SAP102 Is a Highly Mobile MAGUK in Spines.
C. Y. Zheng, R. S. Petralia, Y. X. Wang, B. Kachar, and R. J. Wenthold (2010)
J. Neurosci. 30, 4757-4766
   Abstract »    Full Text »    PDF »
Acute Dynamin Inhibition Dissects Synaptic Vesicle Recycling Pathways That Drive Spontaneous and Evoked Neurotransmission.
C. Chung, B. Barylko, J. Leitz, X. Liu, and E. T. Kavalali (2010)
J. Neurosci. 30, 1363-1376
   Abstract »    Full Text »    PDF »
Pregnanolone Sulfate Promotes Desensitization of Activated NMDA Receptors.
C. L. Kussius, N. Kaur, and G. K. Popescu (2009)
J. Neurosci. 29, 6819-6827
   Abstract »    Full Text »    PDF »
NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission.
F. Espinosa and E. T. Kavalali (2009)
J Neurophysiol 101, 2290-2296
   Abstract »    Full Text »    PDF »
Partitioning the Synaptic Landscape: Distinct Microdomains for Spontaneous and Spike-Triggered Neurotransmission.
M. A. Sutton and E. M. Schuman (2009)
Science Signaling 2, pe19
   Abstract »    Full Text »    PDF »
Synaptic ionotropic glutamate receptors and plasticity are developmentally altered in the CA1 field of Fmr1 knockout mice.
Y. Pilpel, A. Kolleker, S. Berberich, M. Ginger, A. Frick, E. Mientjes, B. A. Oostra, and P. H. Seeburg (2009)
J. Physiol. 587, 787-804
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882