Fast Regulation of GABA A R Diffusion Dynamics by Nogo-A Signaling

Cell Rep. 2019 Oct 15;29(3):671-684.e6. doi: 10.1016/j.celrep.2019.09.015.

Abstract

Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.

Keywords: EI balance; GABAARs; Nogo-A; S1PR2; calcineurin; excitation; inhibition; quantum dots; single particle tracking; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology
  • Calcineurin / metabolism
  • Calcium / metabolism
  • Cells, Cultured
  • Female
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nogo Proteins / immunology
  • Nogo Proteins / metabolism*
  • Patch-Clamp Techniques
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Signal Transduction
  • Sphingosine-1-Phosphate Receptors / antagonists & inhibitors
  • Sphingosine-1-Phosphate Receptors / metabolism
  • Synapses / metabolism
  • Synaptic Transmission

Substances

  • Antibodies, Blocking
  • Nogo Proteins
  • Protein Subunits
  • Receptors, GABA-A
  • Sphingosine-1-Phosphate Receptors
  • sphingosine-1-phosphate receptor-2, mouse
  • Calcineurin
  • Calcium