Editors' ChoiceNeuroscience

Anchors Away

Sci. Signal.  31 Jul 2012:
Vol. 5, Issue 235, pp. ec201
DOI: 10.1126/scisignal.2003447

Both metabotropic, such as mGluR5a, and ionotropic glutamate receptors, such as the N-methyl-D-aspartate (NMDA) receptor, play key roles in synaptic transmission and in synaptic plasticity. Synaptic remodeling, involving induction of protein production, changes in receptor composition, and changes in protein-protein interactions, occurs in dendritic spines in response to sustained synaptic activity. Homer proteins are a family of scaffolding proteins encoded by several genes, which then produce long and short forms of the encoded proteins. Long forms of these proteins multimerize and anchor receptors, such as the mGluRs and NMDA receptors, into macromolecular complexes with other proteins. The short form Homer1a does not multimerize, is induced by sustained synaptic activity, and can disrupt the interaction of proteins with the multimerized Homer scaffold. Moutin et al. used bioluminescence resonance energy transfer (BRET) of transfected HEK293 cells, a human embryonic kidney cell line, and cultured hippocampal neurons to demonstrate that both the long and short Homer proteins interacted with mGluR5a and that these Homer proteins competitively inhibited each other’s interaction with mGluR5a. In the transfected neurons, multimeric Homer showed increased BRET signal in the dendritic spines, whereas the Homer1a signal was similar in the spines and cell body. The BRET signal was reduced between multimeric Homer and mGluR5a in dendritic spines of neurons perfused with a cell-permeable TAT-conjugated form of Homer1a (TAT-Homer1a) but not with those perfused with a mutant version that could not bind to mGluR5a (TAT-HomerW24Y). (TAT is a cell-permeable viral peptide that enables proteins conjugated to this peptide to cross the plasma membrane.) Although imaging of tagged NMDA subunits and mGluR5a showed colocalization of these proteins in dendritic spines, there was no BRET signal indicative of an interaction between these proteins under basal conditions. However, incubation with TAT-Homer1a, but not TAT-HomerW24Y, induced a BRET signal between the NMDA receptor and mGluR5a and decreased NMDA-mediated currents, consistent with an inhibition of NMDA receptor activity by mGluR5a. Sustained activation of NMDA receptors to induce long-term potentiation transiently stimulated increased NMDA receptor currents, increased the abundance of Homer1a transcripts and protein, stimulated BRET signals between NMDA receptors and mGluR5a, and triggered an increase in currents mediated by another type of glutamate receptor, the AMPA receptor. Incubation with TAT-Homer1a immediately after activation of the NMDA receptors abolished the BRET signal between mGluR5a and multimeric Homer and reduced NMDA currents. Thus, induction of a monomeric form of Homer releases mGluR from the multimeric Homer scaffold, which allows mGluR to inhibit NMDA receptor activity.

E. Moutin, F. Raynaud, J. Roger, E. Pellegrino, V. Homburger, F. Bertaso, V. Ollendorff, J. Bockaert, L. Fagni, J. Perroy, Dynamic remodeling of scaffold interactions in dendritic spines controls synaptic excitability. J. Cell Biol. 198, 251–263 (2012). [Abstract] [Full Text]