Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

被引:20
作者
Elmasri, Marwa [1 ]
Hunter, Daniel William [1 ]
Winchester, Giles [1 ]
Bates, Ella Emine [1 ]
Aziz, Wajeeha [1 ]
Van der Does, Does Moolenaar [1 ]
Karachaliou, Eirini [1 ]
Sakimura, Kenji [2 ]
Penn, Andrew Charles [1 ]
机构
[1] Univ Sussex, Sch Life Sci, Sussex Neurosci, Brighton BN1 9QG, E Sussex, England
[2] Niigata Univ, Brain Res Inst, Dept Cellular Neurobiol, Niigata 9518585, Japan
关键词
GRIN2A MUTATIONS; RARE VARIANTS; MICE LACKING; EXPRESSION; PLASTICITY; EPILEPSY; BRAIN; SPECTRUM; APHASIA; DYSREGULATION;
D O I
10.1038/s42003-022-03115-3
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. Here we have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission. The cell-autonomous effect of five severe loss- or gain-of-function GluN2A (NMDA receptor) mutations is assessed on evoked NMDAR-mediated synaptic currents in CA1 pyramidal neurons in cultured mouse hippocampal slices. Data and modelling suggest that mutant-like NMDA-EPSCs can lead to abnormal temporal summation and spine calcium dynamics.
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页数:17
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共 100 条
[1]   Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue [J].
Addis, L. ;
Virdee, J. K. ;
Vidler, L. R. ;
Collier, D. A. ;
Pal, D. K. ;
Ursu, D. .
SCIENTIFIC REPORTS, 2017, 7
[2]   NMDA receptors inhibit synapse unsilencing during brain development [J].
Adesnik, Hillel ;
Li, Guangnan ;
During, Matthew J. ;
Pleasure, Samuel J. ;
Nicoll, Roger A. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (14) :5597-5602
[3]   NMDA Receptor GluN2B (GluRε2/NR2B) Subunit Is Crucial for Channel Function, Postsynaptic Macromolecular Organization, and Actin Cytoskeleton at Hippocampal CA3 Synapses [J].
Akashi, Kaori ;
Kakizaki, Toshikazu ;
Kamiya, Haruyuki ;
Fukaya, Masahiro ;
Yamasaki, Miwako ;
Abe, Manabu ;
Natsume, Rie ;
Watanabe, Masahiko ;
Sakimura, Kenji .
JOURNAL OF NEUROSCIENCE, 2009, 29 (35) :10869-10882
[4]   Visualization of currents in neural models with similar behavior and different conductance densities [J].
Alonso, Leandro M. ;
Marder, Eve .
ELIFE, 2019, 8
[5]   The Decade of the Dendritic NMDA Spike [J].
Antic, Srdjan D. ;
Zhou, Wen-Liang ;
Moore, Anna R. ;
Short, Shaina M. ;
Ikonomu, Katerina D. .
JOURNAL OF NEUROSCIENCE RESEARCH, 2010, 88 (14) :2991-3001
[6]   Subunit-specific NMDA receptor trafficking to synapses [J].
Barria, A ;
Malinow, R .
NEURON, 2002, 35 (02) :345-353
[7]   Fitting Linear Mixed-Effects Models Using lme4 [J].
Bates, Douglas ;
Maechler, Martin ;
Bolker, Benjamin M. ;
Walker, Steven C. .
JOURNAL OF STATISTICAL SOFTWARE, 2015, 67 (01) :1-48
[8]   Rapid bidirectional switching of synaptic NMDA receptors [J].
Bellone, Camilla ;
Nicoll, Roger A. .
NEURON, 2007, 55 (05) :779-785
[9]   Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons [J].
Booker, Sam A. ;
Sumera, Anna ;
Kind, Peter C. ;
Wyllie, David J. A. .
ENEURO, 2021, 8 (04)
[10]   CHARMM: The Biomolecular Simulation Program [J].
Brooks, B. R. ;
Brooks, C. L., III ;
Mackerell, A. D., Jr. ;
Nilsson, L. ;
Petrella, R. J. ;
Roux, B. ;
Won, Y. ;
Archontis, G. ;
Bartels, C. ;
Boresch, S. ;
Caflisch, A. ;
Caves, L. ;
Cui, Q. ;
Dinner, A. R. ;
Feig, M. ;
Fischer, S. ;
Gao, J. ;
Hodoscek, M. ;
Im, W. ;
Kuczera, K. ;
Lazaridis, T. ;
Ma, J. ;
Ovchinnikov, V. ;
Paci, E. ;
Pastor, R. W. ;
Post, C. B. ;
Pu, J. Z. ;
Schaefer, M. ;
Tidor, B. ;
Venable, R. M. ;
Woodcock, H. L. ;
Wu, X. ;
Yang, W. ;
York, D. M. ;
Karplus, M. .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2009, 30 (10) :1545-1614