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

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

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Trans-synaptic Signaling Group, European Neuroscience Institute, 37077 Goettingen, Germany.
German Center for Neurodegenerative Disease, 37075 Goettingen, Germany.
Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, 37075 Goettingen, Germany.
Synaptic Systems GmbH, 37079 Goettingen, Germany.
Brain Research Center and Department of Medicine, University of British Columbia, Vancouver, BC V6T2B5, Canada.
Trans-synaptic Signaling Group, European Neuroscience Institute, 37077 Goettingen, Germany.
Contributed equally


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.

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