| First Author | Wang QW | Year | 2021 |
| Journal | PLoS Biol | Volume | 19 |
| Issue | 7 | Pages | e3001323 |
| PubMed ID | 34228711 | Mgi Jnum | J:308084 |
| Mgi Id | MGI:6727951 | Doi | 10.1371/journal.pbio.3001323 |
| Citation | Wang QW, et al. (2021) Synaptotagmin-7-mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants. PLoS Biol 19(7):e3001323 |
| abstractText | 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. |
