The synaptotagmin protein family has been studied by neuroscientists for decades. However, most isoforms lack well-defined functions. Now, researchers have identified a crucial, presynaptic role for synaptotagmin-3 (SYT3) in the maintenance of reliable, high-frequency, synaptic transmission. They found that it plays a role in accelerating vesicle resupply and enabling the brain to communicate a broad range of signals across synapses.

This work is published in the journal Nature in the article, “Fast resupply of synaptic vesicles requires synaptotagmin-3.

“When brain cells are active, they release neurotransmitters to communicate with their neighbors,” said Skyler Jackman, PhD, assistant scientist in the Vollum Institute at the Oregon Health & Science University. “If a cell is very active it can exhaust its supply of neurotransmitters, which can cause a breakdown of communication and brain disfunction.”

“It turns out that cells have a boost mode that replenishes their supply of neurotransmitters, but until now, we didn’t know the molecule that was responsible,” he said. “We found that SYT3 is directly responsible for that neurotransmitter boost. This gives us new insight about how brains can break down and fail to process information properly.”

The team identified SYT3 as a presynaptic high-affinity Ca2+ sensor, which, they say “drives vesicle replenishment and short-term synaptic plasticity.”

They generated SYT3 knockout mice. In doing so, they found that those mice lacked a robust level of synaptic transmission, compared with control mice. More specifically, synapses in Syt3 knockout mice “exhibited enhanced short-term depression, and recovery from depression was slower and insensitive to presynaptic residual Ca2+. During sustained neuronal firing, SYT3 accelerated vesicle replenishment and increased the size of the readily releasable pool.”

Notably, mutations of the SYT3 gene have been implicated in human cases of epilepsy and autism spectrum disorder. This finding suggests the possibility of developing gene therapies or pharmaceutical approaches targeting SYT3, Jackman said.

“Imbalances in neurotransmitter release are the underlying causes for many neurological disorders,” said Dennis Weingarten, PhD, a postdoctoral researcher in the Jackman lab. In the future, he said, “understanding these molecular switches—such as SYT3—is a crucial step for us to combat these diseases.”

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