Synaptic and Extrasynaptic NMDA Receptor NR2 Subunits in Cultured Hippocampal Neurons
- 1 March 2006
- journal article
- Published by American Physiological Society in Journal of Neurophysiology
- Vol. 95 (3), 1727-1734
- https://doi.org/10.1152/jn.00771.2005
Abstract
Early in development, neurons only express NR1/NR2B-containing N-methyl-d-aspartate (NMDA) receptors. Later, NR2A subunits are upregulated during a period of rapid synapse formation. This pattern is often interpreted to indicate that NR2A-containing receptors are synaptic and that NR2B-containing receptors are extrasynaptic. We re-examined this issue using whole cell recordings in cultured hippocampal neurons. As expected, the inhibition of whole cell currents by the NR2B-specific antagonist, ifenprodil, progressively decreased from 69.5 ± 2.4% [6 days in vitro (DIV)] to 54.9 ± 2.6% (8 DIV), before reaching a plateau in the second week (42.5 ± 2%, 12–19 DIV). In NR2A−/− neurons, which express only NR1/NR2B-containing NMDA receptors, autaptic excitatory postsynaptic currents (EPSCs; ≥12 DIV) were more sensitive to ifenprodil and decayed more slowly than EPSCs in wild-type neurons. Thus NR2B-containing receptors were not excluded from synapses. We blocked synaptic NMDA receptors with MK-801 during evoked transmitter release, thus allowing us to isolate extrasynaptic receptors. Ifenprodil inhibition of this extrasynaptic population was highly variable in different neurons. Furthermore, extrasynaptic receptors in autaptic cultures were only partially blocked by ifenprodil, indicating that NR2A-containing receptors are not exclusively confined to the synapse. Extrasynaptic NR2A-containing receptors were also detected in NR2A−/− neurons transfected with full-length NR2A. Truncation of the NR2A C terminus did not eliminate synaptic expression of NR2A-containing receptors. Our results indicate that NR2A- and NR2B-containing receptors can be located in either synaptic or extrasynaptic compartments.Keywords
This publication has 39 references indexed in Scilit:
- Lack of NMDA Receptor Subtype Selectivity for Hippocampal Long-Term PotentiationJournal of Neuroscience, 2005
- KIF17 Dynamics and Regulation of NR2B Trafficking in Hippocampal NeuronsJournal of Neuroscience, 2003
- Subunit-Specific NMDA Receptor Trafficking to SynapsesNeuron, 2002
- Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathwaysNature Neuroscience, 2002
- Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapseNature, 2001
- Localization and stabilization of ionotropic glutamate receptors at synapses.Cellular and Molecular Life Sciences, 2000
- Distribution, Density, and Clustering of Functional Glutamate Receptors Before and After Synaptogenesis in Hippocampal NeuronsJournal of Neurophysiology, 2000
- Presynaptic Control of Subunit Composition of NMDA Receptors Mediating Synaptic PlasticityJournal of Neuroscience, 1997
- NR2A Subunit Expression Shortens NMDA Receptor Synaptic Currents in Developing NeocortexJournal of Neuroscience, 1997
- Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture.Proceedings of the National Academy of Sciences of the United States of America, 1991