05:38pm Wednesday 15 July 2020

Researchers Discover How Stressed Neurons Recover and Keep Communicating

Ed Chapman led the study.It may be because your synapses, the communication connections between nerve cells, are depressed. Your synapses don’t get sad; they may just be overworked.

Ed Chapman led the study.

But researchers at the University of Wisconsin-Madison have discovered how the body alleviates this “synaptic depression” and lets neurons refuel and be able to keep sending messages via the release of vital neurotransmitters.

There are roughly one million billion synapses in the human brain. If you’re counting, that’s one quadrillion, or 15 zeros. Vesicles, intercellular packets that store molecules like neurotransmitters, release their cargo into the synapse – the gap between a signaling cell and receiving cell. 

Vesicle transport to the membrane and release of neurotransmitters into the synaptic space between neurons is one of the fastest-known chain reactions in biology. Within each communication from one neuron to another, a vesicle inside a cell must fuse with the cell membrane, eject its neurotransmitter cargo into the synapse, and the cargo must attach to a receptor site on the receiving cell to pass on the message.

With so many neurons and so many messages sent and received in the brain, a massive amount of vesicles are used, so busy cells must also constantly be working on replenishing their stores.

Surprise Discovery

In a new study, published today (February 25) in eLife, researchers at the UW School of Medicine and Public Health (SMPH) explain how two proteins, calmodulin and synaptotagmin 7, bind with calcium ions to replenish a neuron’s supply of vesicles.

“During high-frequency transmission, we burn through tons of vesicles, and as a result, the vesicles are depleted and synaptic transmission begins to drop off,” said Dr. Ed Chapman, professor of neuroscience and Howard Hughes Medical Institute investigator at the School of Medicine and Public Health.

“We call it synaptic depression. We believe synaptic depression occurs when we run out of releasable vesicles, or all available sites for synaptic vesicle fusion and transmitter release are ‘clogged up’ and can’t be cleared fast enough to maintain the ongoing transmission.”

The body has mechanisms to revitalize synaptic transmission by either providing more releasable vesicles or by clearing release sites, though the mechanisms are poorly understood. It is known that the replenishment process uses two pathways: one calcium-dependent, the other calcium-independent.

But Chapman’s lab made the unexpected discovery that an ever-present member of the synaptotagmin family, syt 7, is clearly required to activate the calcium-dependent path. It’s the first time identifying the physiological function of syt 7 in neurotransmission, noted Huisheng Liu, a UW-Madison neuroscientist and lead author of the paper.

“After we identified a new player, we sought to see if it interacts with the only other molecule identified in the replenishment pathway, calmodulin, and lo and behold we had another major surprise: of all the syt isoforms we tested, only syt 7 bound to calmodulin,” said Chapman. “It seems the ‘particle’ for calcium ion-dependent replenishment might consist of these two calcium ion-binding proteins.”

This study resolves a level of ambiguity in the field, as existing literature had not led to a definite understanding of the calcium-dependent replenishment process.

A Venue to Address, Resolve and Clarify

Chapman is the first lead author from UW-Madison to publish in eLife, a journal funded by the Howard Hughes Medical Institute, Max Planck Society and Wellcome Trust. Dr. Robert Pugh, professor with the UW Institute for Molecular Virology program, contributed to a previous publication.

Led by Editor-in-Chief and Nobel Prize winner Randy Schekman, eLife was a desirable journal for Chapman to pursue because of its open access policies.

“Contradictions between publications that never seem to be resolved can be addressed here in black and white; it’s a real strength of eLife, and something that is new in biological research journals,” said Chapman. “eLife took a new step by publishing reviews from editors as well as the response to those reviews, which allows biologists an opportunity to address, resolve and clarify discrepancies and disparities. It’s a necessary move for the scientific community.”

University of Wisconsin School of Medicine and Public Health

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