Multidisciplinary work led by Marieke Meijer, team leader at the department of Human Genetics at Amsterdam UMC, shows why synapses are stronger and depress faster in the absence of tomosyns. These results provide new insight into how synapse function is regulated. This study was recently published in Nature Communications.

Synapses respond differently to activity, which is key to how our brain processes information. Some synapses reduce their strength (depression) while others remain stable or even get stronger (facilitation), but the mechanism underlying this process is poorly understood. Meijer and colleagues describe how tomosyns limit synaptic strength at rest to equalize synaptic transmission during activity.

Deciphering synaptic heterogeneity

Synaptic strength depends on the amount of neurotransmitter released from synaptic vesicles by SNARE-mediated membrane fusion. The results from this study show how tomosyns attenuate synaptic strength and offer a new explanation for the functional heterogeneity of synaptic vesicles (‘primed’ vs ‘superprimed’). By limiting the amount of synaptic vesicles that reside in a highly fusogenic ‘superprimed’ state, tomosyns equalize neurotransmission during activity.

"My interest in brain function has led me to specialize on the synapse, the coding unit of the brain."
Marieke Meijer
Team leader at the department of Human Genetics at Amsterdam UMC, location VUmc

Marieke Meijer: "My interest in brain function has led me to specialize on the synapse, the coding unit of the brain. I am fascinated by the intricate molecular machinery that synapses use to tightly control the release of neurotransmitter. Modulation of this machinery results in presynaptic plasticity processes that underlie information processing in the brain. Since realizing that genes I studied out of fundamental interest underly several neuro-developmental and -degenerative disorders, I strive to bridge the fields of synapse biology and clinical genetics by studying fundamental principles and disease mechanisms involving neurotransmitter release."

Exploring the influence of tomosyns

For this multidisciplinary work, Amsterdam Neuroscientists Marieke Meijer, Miriam Öttl and Matthijs Verhage from the Center for Neurogenomics and Cognitive Research (CNCR) teamed up with biophysicists Yongli Zhang and Jie Yang from Yale University, USA. The researchers combined synapse physiology on cultured neurons from a conditional mouse model of tomosyn deficiency with single-molecule force measurements. Together, their data reveal that tomosyns produce a new intermediate state in SNARE assembly which drastically reduces the probability that synaptic vesicles fuse.

Translation of research findings

This study brings new insight into how synapse function can be regulated at the molecular level. In the future, this provides a mechanistic framework for our understanding of synapse-related brain disorders and could advance the development of new therapeutic targets.

Read the full paper in Nature Communications.

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This research was sponsored by a ZonMw-Veni grant to Marieke Meijer from the NWO talent program in 2019.
The header image is created by local artist Rini Brakkee who, inspired by this research, started to paint the invisible events in the human brain.