TY - UNPB

T1 - Synaptotagmin 7 docks synaptic vesicles for Doc2α-triggered asynchronous neurotransmitter release

AU - Wu, Zhenyong

AU - Kusick, Grant

AU - Berns, Manon

AU - Raychaudhuri, Sumana

AU - Itoh, Kie

AU - Walter, Alexander

AU - Chapman, Edwin

AU - Watanabe, Shigeki

PY - 2022

Y1 - 2022

N2 - The molecular basis of asynchronous neurotransmitter release remains enigmatic despite decades of intense study. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses from cultured neurons and acute slices, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot recover on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse on during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus ‘feeding’ synaptic vesicles to Doc2 for asynchronous release during ongoing transmission

AB - The molecular basis of asynchronous neurotransmitter release remains enigmatic despite decades of intense study. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses from cultured neurons and acute slices, Doc2α is the major Ca2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot recover on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse on during repetitive activity. By contrast, synapses lacking Doc2α have normal activity-dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus ‘feeding’ synaptic vesicles to Doc2 for asynchronous release during ongoing transmission

U2 - 10.1101/2022.04.21.489101

DO - 10.1101/2022.04.21.489101

M3 - Preprint

BT - Synaptotagmin 7 docks synaptic vesicles for Doc2α-triggered asynchronous neurotransmitter release

ER -