Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting

Science. 2019 Jan 4;363(6422):eaav1483. doi: 10.1126/science.aav1483. Epub 2018 Dec 13.

Abstract

Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / physiology
  • Cells, Cultured
  • Endocytosis*
  • Female
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Long-Term Potentiation
  • Long-Term Synaptic Depression
  • Male
  • Maze Learning
  • Memory*
  • Mice
  • Mice, Knockout
  • Neurons / physiology
  • Protein Transport
  • Rats, Wistar
  • Receptors, AMPA / physiology*
  • Subcellular Fractions
  • Synapses / physiology*
  • Synaptic Vesicles
  • Synaptosomes
  • Synaptotagmins / genetics
  • Synaptotagmins / physiology*
  • Transfection

Substances

  • Receptors, AMPA
  • Syt3 protein, mouse
  • Synaptotagmins
  • Calcium

Grant support