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Understanding Synaptotagmin-7’s Place in Bipolar Disorder

A new study by researchers at Tsinghua University have uncovered an important mechanism in bipolar disorder involving the disruption of a spontaneous neurotransmitter, Syt7.

Bipolar disorder is a mental disorder defined by sporadic episodes of mania and depression that can affect one’s ability to carry out everyday activities or nurture relationships. According to the World Health Organization, about 45 million individuals worldwide are affected by this complex neuropsychiatric disorder.

In a new study published in PLOS Biology, Jun Yao and colleagues at Tsinghua University report that the calcium sensor Synaptotagmin-7 (Syt7) drives the activation of spontaneous N-methyl-D-aspartate receptor (NMDAR) currents that essentially contribute to mental illness.

Neurotransmitters are chemical messengers that transmit signals across a synapse from neurons to target cells. Such chemical release is driven by calcium ion signals. There are two types of calcium-dependent release: action potential (AP)-evoked release and AP-independent spontaneous release. While the AP-evoked neurotransmitter release is essential in transmitting neuronal signals to downstream cells, spontaneous release has been found to play crucial roles in a range of neural functions such as neurodevelopment, brain homeostasis, and neurological disorders. Presently, it is known that there are at least two proteins, Syt1 and Doc2, that can act as calcium sensors and drive spontaneous release.

From their previous work, Yao and colleagues have reported that calcium sensor Syt7 specifically triggered glutamate release, which plays a crucial role in the initiation of bipolar-like behavioural abnormalities in mice. This prompted them to look deeper into the role of Syt7 in spontaneous synaptic vesicle release.

In the present study, the team first utilised the CRISPR interference gene knockdown technique to silence the two candidate proteins, Syt1 and Doc2, from releasing glutamate spontaneously. However, they were still able to observe a considerable amount of spontaneous release events. The researchers then went on to inactivate Syt7 and reported that the frequency of spontaneous release was largely reduced. This suggests that Syt7 probably functioned in the spontaneous release of glutamate.

As Syt7 induces membrane fusion by responding to calcium and strontium ions, the research team analysed brain slices and found that they could induce changes in spontaneous release by replacing extracellular calcium with strontium ions. When they made the switch, the spontaneous release was enhanced in the wild-type neurons but was reduced in the Syt7-deficient neurons. The team also measured calcium ion dose-response to spontaneous release and disrupted Syt7’s calcium-binding activity. The obtained results further support the theory that Syt7 operate as a third calcium sensor to promote the spontaneous release of glutamate.

Next, the team investigated the physiological function of Syt7-triggered spontaneous glutamate release. Based on their previous study, they established that Syt7 deficiency induces GluN2B-NMDAR hypoactivity that contribute to the induction of bipolar disorder-like behaviours. When compared to 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. In addition, altering the localisation of Syt7 within the release site still allowed Syt7 to trigger spontaneous release, but positional non-correspondence diminished the activation of the GluN2B-NMDARs. Hence, by activating the GluN2B-NMDARs, Syt7-triggered spontaneous glutamate release can be said to be involved in bipolar disorder.

As it has been previously suggested that spontaneous glutamate release may activate different populations of NMDARs and thus leading to differing responses to a well-known NMDAR-targeted anti-depressant, Yao’s study not only provides direct evidence that NMDARs are unlikely to be saturated by spontaneous release but that Syt7 could be partly responsible for neuropsychiatric disorders. [APBN]

Source: Wang et al. (2021). Synaptotagmin-7–mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants. PLoS biology, 19(7), e3001323.