GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization

The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) through a previously unknow...

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Bibliographic Details
Published in:The Journal of neuroscience 2011-01, Vol.31 (3), p.819-833
Main Authors: Zhou, Zikai, Hu, Jim, Passafaro, Maria, Xie, Wei, Jia, Zhengping
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Blotting, Western
CA1 Region, Hippocampal - cytology
CA1 Region, Hippocampal - physiology
Cadherins - metabolism
Cells, Cultured
Cofilin 1 - metabolism
Electrophysiology
Long-Term Synaptic Depression - physiology
Mice
Mice, Transgenic
Neurons - cytology
Neurons - metabolism
Receptors, AMPA - metabolism
Receptors, Metabotropic Glutamate - metabolism
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Summary:The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) through a previously unknown mechanism involving N-cadherin-dependent and cofilin-mediated actin reorganization. We show that GluA2 is indispensable for mGluR-LTD in the hippocampus, and surprisingly this action of GluA2 is mediated by its extracellular domain interaction with N-cadherin. Accordingly, we show that the function of N-cadherin is regulated by and required for mGluR-LTD. Furthermore, we show that the regulatory effect of GluA2/N-cadherin is mediated through activation of Rho GTPase Rac1 and its downstream actin regulator cofilin, and, importantly, the requirement for GluA2/N-cadherin can be overcome by manipulating cofilin. These results provide compelling evidence that the extracellular domain of GluA2 regulates long-lasting synaptic plasticity through a signaling mechanism that is distinct from those used by the other domains of the receptor subunit.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.3869-10.2011