Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP

Dick Wu, Taulant Bacaj, Wade Morishita, Debanjan Goswami, Kristin L. Arendt, Wei Xu, Lu Chen, Robert C. Malenka () and Thomas C. Südhof ()
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Dick Wu: Stanford University Medical School
Taulant Bacaj: Stanford University Medical School
Wade Morishita: Nancy Pritzker Laboratory, Stanford University Medical School
Debanjan Goswami: Nancy Pritzker Laboratory, Stanford University Medical School
Kristin L. Arendt: Stanford University Medical School
Wei Xu: Stanford University Medical School
Lu Chen: Stanford University Medical School
Robert C. Malenka: Nancy Pritzker Laboratory, Stanford University Medical School
Thomas C. Südhof: Stanford University Medical School

Nature, 2017, vol. 544, issue 7650, 316-321

Abstract: Abstract Strengthening of synaptic connections by NMDA (N-methyl-d-aspartate) receptor-dependent long-term potentiation (LTP) shapes neural circuits and mediates learning and memory. During the induction of NMDA-receptor-dependent LTP, Ca2+ influx stimulates recruitment of synaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, thereby strengthening synapses. How Ca2+ induces the recruitment of AMPA receptors remains unclear. Here we show that, in the pyramidal neurons of the hippocampal CA1 region in mice, blocking postsynaptic expression of both synaptotagmin-1 (Syt1) and synaptotagmin-7 (Syt7), but not of either alone, abolished LTP. LTP was restored by expression of wild-type Syt7 but not of a Ca2+-binding-deficient mutant Syt7. Blocking postsynaptic expression of Syt1 and Syt7 did not impair basal synaptic transmission, reduce levels of synaptic or extrasynaptic AMPA receptors, or alter other AMPA receptor trafficking events. Moreover, expression of dominant-negative mutant Syt1 which inhibits Ca2+-dependent presynaptic vesicle exocytosis, also blocked Ca2+-dependent postsynaptic AMPA receptor exocytosis, thereby abolishing LTP. Our results suggest that postsynaptic Syt1 and Syt7 act as redundant Ca2+-sensors for Ca2+-dependent exocytosis of AMPA receptors during LTP, and thereby delineate a simple mechanism for the recruitment of AMPA receptors that mediates LTP.

Date: 2017
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DOI: 10.1038/nature21720

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