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Related Experiment Video

Updated: Jan 16, 2026

Single Synapse Indicators of Glutamate Release and Uptake in Acute Brain Slices from Normal and Huntington Mice
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Activity Deprivation Modulates the Shank3/Homer1/mGluR5 Signaling Pathway to Enable Synaptic Upscaling.

Andrea A Guerrero1, Gina G Turrigiano2

  • 1Department of Biology, Brandeis University, Waltham, Massachusetts 02453.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|October 3, 2025
PubMed
Summary

Shank3 dephosphorylation enables synaptic upscaling by promoting specific metabotropic glutamate receptor signaling. This reveals distinct molecular mechanisms for synaptic up- and downscaling.

Keywords:
Shank3homeostatic plasticitymGluRsynaptic plasticitysynaptic scaling

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Shank3 protein is crucial for synaptic scaling, a homeostatic plasticity mechanism.
  • Activity-dependent Shank3 phosphorylation/dephosphorylation at S1586/S1615 regulates synaptic upscaling.
  • Shank3 interacts with Homer1, which links to metabotropic glutamate receptors (mGluRs).

Purpose of the Study:

  • To investigate the molecular mechanisms downstream of Shank3 dephosphorylation in synaptic upscaling.
  • To elucidate the role of Homer1 and mGluR signaling in Shank3-mediated synaptic plasticity.

Main Methods:

  • Utilized cultured rat neurons.
  • Employed phosphomimetic Shank3 mutants to assess binding and interaction.
  • Manipulated mGluR1 and mGluR5 signaling using competitive and noncompetitive inhibitors.
  • Investigated signaling pathways downstream of Group I mGluRs.

Main Results:

  • Phosphomimetic Shank3 showed reduced binding to long-form Homer1.
  • Competitive inhibition of mGluR signaling, but not noncompetitive, impaired synaptic upscaling.
  • mGluR5 activation rescued synaptic upscaling in phosphomimetic Shank3 mutants.
  • Identified specific signaling pathways downstream of Group I mGluRs essential for upscaling.

Conclusions:

  • Activity-dependent Shank3 dephosphorylation reconfigures the Shank3/Homer1/mGluR pathway to favor agonist-dependent mGluR signaling, enabling synaptic upscaling.
  • Synaptic upscaling and downscaling utilize distinct functional states of the same signaling components (Shank3, Homer1, mGluR5).