The National Institute of Information and Communications Technology (NICT, President: OHNO Hideo, Ph.D.) has discovered molecular mechanism of synaptic facilitation, instantaneous strengthening of synaptic transmission, which may be physiological basis of instantaneous memory. Synaptic facilitation has been known for a long time and studied by major physiologists. However, its mechanism and its biological meaning still remain ambiguous. This study revealed that intramolecular interaction of a calcium binding protein, Synaptotagmin 7 (Syt7) functions for synaptic facilitation, and the interaction between Syt7 domains is required for memory. This study using a fruit fly, Drosophila melanogaster , which is a model animal for genetic analysis, provides an insight for general mechanism of memory, which may suggest new designs of future ICT. Since this is the first elucidation of molecular mechanism of Syt7, this study has the potential in the future to be applied to diseases, which has been reported to be related to Syt7.
This achievement appeared in the “ Calcium sensing by C2A domain of Synaptotagmin 7 is required through the linker for both synaptic facilitation and memory ”, in Proceeding of the National Academy of Sciences of the United States of America on September 21, 2026.
We remember what we have just seen, or what we have just heard. However, we don’t know mechanism of the instantaneous memory. We have discovered the molecular mechanism, which can be a basis for the instantaneous memory.
We have focused on “synaptic facilitation”, where repetitive action potential enlarges synaptic transmission gradually. Although synaptic facilitation has been studied by major physiologists, its mechanism and biological significance in the brain has not been well known. We have performed extensive analysis of Syt7 mutants, taking advantage of Drosophila (fruit flies) embryonic neuromuscular synapses, which is still highly plastic and amenable to sophisticated genetic analysis. Through the analysis, we found that residual calcium after the previous action potential binds to the C2A domain of Syt7, releasing C2B-mediated suppression of transmission, resulting in enhancement of transmitter release (see Figure 1). Such intramolecular interaction was revealed through extensive analysis of Drosophila Syt7 mutants. Mutants with defects in the intramolecular interaction showed severe phenotype not only in facilitation, but also in memory, which is assayed through our Pavlovian conditioning system (Sakurai et al., Current Biology , 2021). These results are consistent with the possibility that synaptic facilitation is actually manifestation of instantaneous memory. This possibility would be consistent with the switching mechanism through Syt7 intramolecular interaction would be quick and facilitation also occurs instantaneously.
Beyond a basic mechanism of memory, this study provides an important suggestion to medical application because this study is the first elucidation of how Syt7 functions for regulating vesicle fusion. For example, it is reported that some patients of bipolar disorder have downregulated expression of Syt7. Our study would give a mechanistic insight into the disease if we imagine Syt7 is suppressing and releasing neuromodulators in the patients. Suppression of Syt7 in bipolar disorder patients might be reduced, leading to excessive release of neuromodulators such as serotonin or dopamine. Thus, this study may open an avenue for medical care of Syt7-related diseases.
Synaptic facilitation in this study is a phenomenon restricted to the presynaptic terminals. However, postsynaptic activity is also involved in long-term memory. Thus, the coupling of the postsynaptic activity to the presynaptic facilitation in this study, as proposed by our previous study (Yoshihara et al., Science , 2005; see Figure 2), would give a further insight into the general principle of memory in the future.
Authors: Akira Sakurai, Takaaki Fujii and Motojiro Yoshihara
Title: Calcium sensing by C2A domain of Synaptotagmin 7 is required through the linker for both synaptic facilitation and memory
Journal: Proceedings of the National Academy of Sciences of the United States of America
DOI: 10.1073/pnas.2528214123
URL: https://doi.org/10.1073/pnas.2528214123
The study was supported by the following funding agencies:
JSPS (JP19H00998, 22H00420, 25H00996, JP19K16275, 22K06439, 25H02530)
Proceedings of the National Academy of Sciences
Experimental study
Cells
Calcium sensing by C2A domain of Synaptotagmin 7 is required through the linker for both synaptic facilitation and memory
21-Sep-2026