Synaptotagmin 2 Is the Fast Ca2+ Sensor at a Central Inhibitory Synapse

Cell Rep. 2017 Jan 17;18(3):723-736. doi: 10.1016/j.celrep.2016.12.067.


GABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca2+ sensor of exocytosis at GABAergic basket cell (BC) to Purkinje cell (PC) synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ∼10%, identifying Syt2 as the major Ca2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits.

Keywords: Ca(2+) sensor; GABAergic synapses; basket cells; cerebellum; endocytosis; exocytosis; feedforward inhibition; pool replenishment; synaptotagmin; transmitter release.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Calcium / metabolism*
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Evoked Potentials / drug effects
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Phosphinic Acids / pharmacology
  • Purkinje Cells / metabolism
  • Pyridines / pharmacology
  • Synapses / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptotagmin I / genetics
  • Synaptotagmin I / metabolism
  • Synaptotagmin II / deficiency
  • Synaptotagmin II / genetics*
  • Synaptotagmin II / metabolism


  • (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid
  • Phosphinic Acids
  • Pyridines
  • Synaptotagmin I
  • Synaptotagmin II
  • Calcium