Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 3, Pages 1038-1043Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0711412105
Keywords
glutamate; hippocampus; plasticity; synapse; trafficking
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Funding
- NIMH NIH HHS [R37 MH063394, 5 R37 MH063394] Funding Source: Medline
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Excitatory synapses in the mammalian brain contain two types of ligand-gated ion channels: AMPA receptors (AMPARs) and NMDA receptors (NMDARs). AMPARs are responsible for generating excitatory synaptic responses, whereas NMDAR activation triggers long-lasting changes in these responses by modulating the trafficking of AMPARs toward and away from synapses. AMPARs are tetramers composed of four subunits (GIuR1-GIuR4), which current models suggest govern distinct AMPAR trafficking behavior during synaptic plasticity. Here, we address the roles of GluR2 and GIuR3 in controlling the recycling- and activity-dependent endocytosis of AMPARs by using cultured hippocampal neurons prepared from knockout (KO) mice lacking these subunits. We find that synapses and dendritic spines form normally in cells lacking GIuR2/3 and that upon NMDAR activation, GIuR2/3-lacking AMPARs are endocytosed in a manner indistinguishable from GIuR2-containing AMPARs in wild-type (WT) neurons. AMPARs lacking GIuR2/3 also recycle to the plasma membrane identically to WT AMPARs. However, because of their permeability to calcium, GIuR2-lacking but not WT AMPARs exhibited robust internalization throughout the dendritic tree in response to AMPA application. Dendritic endocytosis of AMPARs also was observed in GABAergic neurons, which express a high proportion of GIuR2-lacking AMPARs. These results demonstrate that GluR2 and GIuR3 are not required for activity-dependent endocytosis of AMPARs and suggest that the most important property of GluR2 in the context of AMPAR trafficking may be its influence on calcium permeability.
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