Nanoscale Subsynaptic Domains Underlie the Organization of the Inhibitory Synapse

Cell Rep. 2019 Mar 19;26(12):3284-3297.e3. doi: 10.1016/j.celrep.2019.02.070.


Inhibitory synapses mediate the majority of synaptic inhibition in the brain, thereby controlling neuronal excitability, firing, and plasticity. Although essential for neuronal function, the central question of how these synapses are organized at the subsynaptic level remains unanswered. Here, we use three-dimensional (3D) super-resolution microscopy to image key components of the inhibitory postsynaptic domain and presynaptic terminal, revealing that inhibitory synapses are organized into nanoscale subsynaptic domains (SSDs) of the gephyrin scaffold, GABAARs and the active-zone protein Rab3-interacting molecule (RIM). Gephyrin SSDs cluster GABAAR SSDs, demonstrating nanoscale architectural interdependence between scaffold and receptor. GABAAR SSDs strongly associate with active-zone RIM SSDs, indicating an important role for GABAAR nanoscale organization near sites of GABA release. Finally, we find that in response to elevated activity, synapse growth is mediated by an increase in the number of postsynaptic SSDs, suggesting a modular mechanism for increasing inhibitory synaptic strength.

Keywords: GABA(A) receptor; RIM; VGAT; gephyrin; homeostatic plasticity; inhibitory synapse; structured illumination microscopy; super-resolution nanoscopy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Membrane Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Presynaptic Terminals / metabolism*
  • Rats
  • Receptors, GABA-A / metabolism*
  • gamma-Aminobutyric Acid / metabolism*


  • Membrane Proteins
  • Receptors, GABA-A
  • gephyrin
  • gamma-Aminobutyric Acid