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Insight into Brain Function and Malfunctions

Summary: The study identifies the synaptotagmin-3 (SYT3) protein as a key molecule that allows synaptic transmission. The findings could help develop treatments for a number of neurological disorders, including ASD and epilepsy.

Source: Oregon Health and Science University

Scientists at Oregon Health and Science University have identified a long-sought gene-encoded protein that enables the brain to transmit a wide range of signals between spaces between neurons known as a synapse.

The discovery, published today in the journal Nature.

The protein, known as synaptotagmin-3 or SYT3, helps replenish the supply of chemical neurotransmitters that carry signals between neurons.

“When brain cells are active, they release neurotransmitters to communicate with their neighbors,” said senior author Skyler Jackman, assistant scientist at the OHSU Vollum Institute. “If a cell is too active, it can deplete its supply of neurotransmitters, causing impaired communication and brain dysfunction.

“It turned out to be a mode of support that replenishes cells’ neurotransmitter supply, but until now we didn’t know the molecule responsible. We found that SYT3 is directly responsible for this neurotransmitter increase,” he said. “This gives us new insight into how brains can break down and not process information properly.”

The researchers produced “knockout” mice that lacked the SYT3 gene. They found that these mice lacked a more robust level of synaptic transmission compared to control mice with the gene.

The protein, known as synaptotagmin-3 or SYT3, helps replenish the supply of chemical neurotransmitters that carry signals between neurons. image public domain

In particular, mutations of the SYT3 gene have been implicated in cases of human epilepsy and autism spectrum disorder. Jackman said research published today suggests the possibility of developing gene therapies or pharmaceutical approaches that target SYT3.

“Imbalances in neurotransmitter release are underlying causes of many neurological disorders,” said lead author Dennis Weingarten, a postdoctoral researcher in the Jackman lab. In the future, “Understanding these molecular switches like SYT3 is a crucial step towards fighting these diseases,” he said.

Jackman’s lab specializes in the study of synaptic transmission. The human brain contains hundreds of trillions of synapses. Discovering the molecules that give these special structures unique properties is crucial to understanding brain function and neurological disorders.

“Synaptic transmission is essential for perceiving our environment, making decisions, and picking up nearly every other aspect of our inner world,” said Jackman.

Financing: This work was supported by the Whitehall Foundation, the Medical Research Foundation, and the National Institutes of Health Imaging Core Facility with the P30NS061800 award.

About this neuroscience research news

Author: Erik Robinson
Source: Oregon Health and Science University
Communication: Erik Robinson – Oregon Health and Science University
Picture: image public domain

Original research: Closed access.
“Rapid resupply of synaptic vesicles requires synaptotagmin-3” by Skyler Jackman et al. Nature

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Abstract


Rapid feeding of synaptic vesicles requires synaptotagmin-3

Sustained neuronal activity requires rapid refeeding of synaptic vesicles to maintain reliable synaptic transmission. The regeneration of these vesicles is accelerated by submicromolar presynaptic Ca.2+ yet unidentified high-affinity Ca2+ you ask.

Here we define synaptotagmin-3 (SYT3) as presynaptic high-affinity Ca.2+ sensor that ensures vesicle regeneration and short-term synaptic plasticity. synapses Syt3 knockout mice showed increased short-term depression and slower recovery from depression and were insensitive to presynaptic residual Ca.2+.

During sustained neuronal firing, SYT3 accelerated vesicle regeneration and increased the size of the readily released pool. SYT3 also mediated short-term facilitation under conditions of low probability of release and promoted synaptic enhancement together with another high-affinity synaptotagmin, SYT7 (ref.).

Biophysical modeling predicted that SYT3 mediates both regeneration and facilitation by promoting the transition of loosely located vesicles to tightly located, ready states.

Our results reveal a crucial role for presynaptic SYT3 in maintaining reliable high-frequency synaptic transmission. Moreover, multiple forms of short-term plasticity can converge on Ca, a reversible mechanism.2+-dependent vesicle placement.

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