Abstract
Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.
Highlights
Neurotransmitter release is driven by an increase in intracellular Ca2+
It has been suggested that Syt7 and Syt1 were redundant Ca2+ sensors for postsynaptic AMPA receptor (AMPAR) trafficking that underlie an important mechanism for the induction of long-term potentiation (LTP) [22]
It has been reported that Syt7 KO hippocampal neurons have no apparent changes in the rate of spontaneous release [19], we were interested to know whether Syt7 could be a redundant Ca2+ sensor with Syt1 and Doc2
Summary
Three types of Ca2+dependent release have been identified: Action potential (AP) evoked fast synchronous release, slow asynchronous release, and AP-independent spontaneous release [1,2]. All these types are triggered by the orchestration of the SNARE complex, consisting of the v-SNARE synaptobrevin-2 (Syb2), the t-SNAREs syntaxin-1A (Stx1a) and SNAP-25, and their respective Ca2+ sensor proteins [3,4,5,6,7,8,9,10]. The synaptotagmins are a family of proteins that contain a transmembrane domain and 2 tandom C2 domains called C2A and C2B. Doc is a cytosolic protein containing 2 C2 domains without a transmembrane domain
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