MicroRNA regulation of homeostatic synaptic plasticity

Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11650-5. doi: 10.1073/pnas.1017576108. Epub 2011 Jun 22.


Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Conserved Sequence
  • Dendritic Spines / metabolism
  • Gene Knockdown Techniques
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Homeostasis
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / genetics*
  • Neuronal Plasticity / physiology*
  • Presynaptic Terminals / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Stability
  • Rats
  • Sequence Homology, Nucleic Acid


  • 3' Untranslated Regions
  • Membrane Glycoproteins
  • MicroRNAs
  • Nerve Tissue Proteins
  • Sv2a protein, rat