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N-methyl-d-aspartate receptors (NMDARs) are fundamental coincidence detectors of synaptic activity necessary for the induction of synaptic plasticity and synapse stability. Adjusting NMDAR synaptic content, whether by receptor insertion or lateral diffusion between extrasynaptic and synaptic compartments, could play a substantial role defining the characteristics of the NMDAR-mediated excitatory postsynaptic current (EPSC), which in turn would mediate the ability of the synapse to undergo plasticity. Lateral NMDAR movement has been observed in dissociated neurons; however, it is currently unclear whether NMDARs are capable of lateral surface diffusion in hippocampal slices, a more physiologically relevant environment. To test for lateral mobility in rat hippocampal slices, we rapidly blocked synaptic NMDARs using MK-801, a use-dependent and irreversible NMDAR blocker. Following a 5-min washout period, we observed a strong recovery of NMDAR-mediated responses. The degree of the observed recovery was proportional to the amount of induced blockade, independent of levels of intracellular calcium, and mediated primarily by GluN2B-containing NMDA receptors. These results indicate that lateral diffusion of NMDARs could be a mechanism by which synapses rapidly adjust parameters to fine-tune synaptic plasticity. NEW & NOTEWORTHY N-methyl-d-aspartate-type glutamate receptors (NMDARs) have always been considered stable components of synapses. We show that in rat hippocampal slices synaptic NMDARs are in constant exchange with extrasynaptic receptors. This exchange of receptors is mediated primarily by NMDA receptors containing GluN2B, a subunit necessary to undergo synaptic plasticity. Thus this lateral movement of synaptic receptors allows synapses to rapidly regulate the total number of synaptic NMDARs with potential consequences for synaptic plasticity.
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This content will become publicly available on January 22, 2026
Activity-Dependent Internalization of Glun2B-Containing NMDARs Is Required for Synaptic Incorporation of Glun2A and Synaptic Plasticity
NMDA-type glutamate receptors are heterotetrameric complexes composed of two GluN1 and two GluN2 subunits. The precise composition of the GluN2 subunits determines the channel's biophysical properties and influences its interaction with postsynaptic scaffolding proteins and signaling molecules involved in synaptic physiology and plasticity. The precise regulation of NMDAR subunit composition at synapses is crucial for proper synaptogenesis, neuronal circuit development, and synaptic plasticity, a cellular model of memory formation. In the forebrain during early development, NMDARs contain solely the GluN2B subunit, which is necessary for proper synaptogenesis and synaptic plasticity. In rodents, GluN2A subunit expression begins in the second postnatal week, replacing GluN2B-containing NMDARs at synapses in an activity- or sensory experience-dependent process. This switch in NMDAR subunit composition at synapses alters channel properties and reduces synaptic plasticity. The molecular mechanism regulating the switch remains unclear. We have investigated the role of activity-dependent internalization of GluN2B-containing receptors in shaping synaptic NMDAR subunit composition. Using molecular, pharmacological, and electrophysiological approaches in cultured organotypic hippocampal slices from rats of both sexes, we show that the process of incorporating GluN2A-containing NMDAR receptors requires activity-dependent internalization of GluN2B-containing NMDARs. Interestingly, blockade of GluN2A synaptic incorporation was associated with impaired potentiation of AMPA-mediated synaptic transmission, suggesting a potential coupling between the trafficking of AMPARs into synapses and that of GluN2A-containing NMDARs. These insights contribute to our understanding of the molecular mechanisms underlying synaptic trafficking of glutamate receptors and synaptic plasticity. They may also have implications for therapeutic strategies targeting NMDAR function in neurological disorders.
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- Award ID(s):
- 2224262
- PAR ID:
- 10626957
- Publisher / Repository:
- NSF Public Access Repository
- Date Published:
- Journal Name:
- The Journal of Neuroscience
- Volume:
- 45
- Issue:
- 4
- ISSN:
- 0270-6474
- Page Range / eLocation ID:
- e0823242024
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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