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A new study elucidates an important mechanism of bipolar disorder involving the disruption of spontaneous neurotransmitter release in PLOS Biology

2021-07-09 17:52:27

In a paper published online in the PLOS Biology on July 6, 2021, Jun Yao and coauthors of Tsinghua University reported their findings in the mechanism involving the deficits of Synaptotagmin-7-mediated activation of spontaneous NMDAR currents in bipolar disorder (BD), which is a complex neuropsychiatric disorder characterized by intermittent episodes of mania and depression.

Neurotransmitter release usually has two subtypes, including the action potential (AP)-evoked release and AP-independent spontaneous release, which is still triggered by Ca2+ signals. While the AP-evoked neurotransmitter release plays a crucial role in the transduction of neuronal signals to the downstream cells, spontaneous has been found to play important roles in a variety of neural functions such as neurodevelopment, brain homeostasis and neurological disorders. In the past twenty years, two candidate proteins have been found to act as Ca2+ sensor to trigger spontaneous release.

Previously, Yao and coauthors have reported that glutamate release specifically triggered by Synaptotagmin-7 (Syt7) plays an important role in the induction of bipolar-like behavioral abnormalities in mice. In this study, the authors first utilized the CRISPR interference gene knockdown technique to silence the two candidate Ca2+ sensors for spontaneous glutamate release, and still observed a large amount of spontaneous release events. Based on this, the authors further inactivated Syt7 and observed that the frequency of spontaneous release was largely diminished. This result indicated that Syt7 likely functioned in spontaneous release. As Syt7 has a very unique characteristic that it can respond to not only Ca2+ but also Sr2+ to induce membrane fusion, the authors analyzed in the brain slices the changes in spontaneous release induced by rapidly substituting extracellular Ca2+ with Sr2+. They found that following the Ca2+/Sr2+ switch, the spontaneous release was enhanced in the wild-type neurons but it was attenuated in the Syt7-deficient neurons. The authors further tested the performances of Syt7 mutants with Ca2+ binding activity abolished and Ca2+ dose response to spontaneous release. All results supported that Syt7 acted as a third Ca2+ sensor to drive spontaneous glutamate release.

Then, the authors investigated that physiological function of Syt7-triggered spontaneous glutamate release. Based on their finding in 2020 that Syt7 deficiency induces GluN2B-NMDAR deficits that contribute to the induction of BD-like behaviors, the authors soon discovered that compared to the non-Syt7-triggered spontaneous release events, the Syt7-dependent events that occurred in the peripheral synaptic region could efficiently activate the juxtaposed postsynaptic GluN2B-NMDARs. Moreover, modifying the localization of Syt7 within the release site still allowed Syt7 to trigger spontaneous release, but the positional non-correspondence abolished the activation of the GluN2B-NMDARs. Hence, Syt7-triggered spontaneous glutamate release was involved in bipolar disorder through activating the GluN2B-NMDARs.

The involvement of Syt7 deficits in BD was initially discovered by the authors using induced pluripotent stem cell (iPSC) technology, and later they identified several Syt7 mutations in BD patients. Thus, the authors investigated the performance of these mutations using the iPSC model of BD, and found that they could no longer activate GluN2B-NMDARs through spontaneous release in BD patient iPSC-derived neurons. The authous therefore concluded that Syt7 acts as a Ca2+ sensor for a subpopulation of spontaneous release events with a unique physiological role in bipolar disorder.

Dr. Jun Yao, from the State Key Laboratory of Membrane Biology, School of Life Sciences; Tsinghua-Peking Joint Center for Life Sciences, McGovern Institute for Brain Research, Tsinghua University, is the corresponding author of the paper. Dr. Qiu-Wen Wang is the first author of the paper. All other co-authors made significant contributions to this study.

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Figure 1. Syt7-triggered spontaneous glutamate release in the peripheral active zone efficiently activates postsynaptic GluN2B-containing NMDARs.