REST/NRSF drives homeostatic plasticity of inhibitory synapses in a target-dependent fashion

Elife. 2021 Dec 2:10:e69058. doi: 10.7554/eLife.69058.


The repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) controls hundreds of neuron-specific genes. We showed that REST/NRSF downregulates glutamatergic transmission in response to hyperactivity, thus contributing to neuronal homeostasis. However, whether GABAergic transmission is also implicated in the homeostatic action of REST/NRSF is unknown. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Notably, this effect is limited to inhibitory-onto-excitatory neuron synapses, whose density increases at somatic level and decreases in dendritic regions, demonstrating a complex target- and area-selectivity. The upscaling of perisomatic inhibition was occluded by TrkB receptor inhibition and resulted from a coordinated and sequential activation of the Npas4 and Bdnf gene programs. On the opposite, the downscaling of dendritic inhibition was REST-dependent, but BDNF-independent. The findings highlight the central role of REST/NRSF in the complex transcriptional responses aimed at rescuing physiological levels of network activity in front of the ever-changing environment.

Keywords: BDNF; GABAergic synapses; NPAS4; REST/NRSF; homeostatic plasticity; mouse; neural hyperactivity; neuroscience; synaptic homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • GABA Agents
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Homeostasis
  • Inhibitory Postsynaptic Potentials / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / metabolism*
  • Neurons / physiology
  • Receptor, trkB / metabolism
  • Repressor Proteins / metabolism*
  • Synapses / metabolism
  • Transcription Factors


  • GABA Agents
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Transcription Factors
  • Green Fluorescent Proteins
  • Receptor, trkB

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.