Study reveals function of little-understood synapse in the brain

New research from Oregon Health and Science University reveals for the first time the function of a little-understood junction between brain cells that could have important therapeutic implications for diseases ranging from sclerosis in plaques to Alzheimer’s disease, to a type of brain cancer known as glioma.

The study is published in Natural neuroscience.

Neuroscientists have focused on the junction, or synapse, connecting neurons to a non-neuronal cell, known as oligodendrocyte precursor cells, or OPCs. OPCs can differentiate into oligodendrocytes, which produce a sheath around nerves called myelin. Myelin is the protective sheath covering each nerve cell’s axon, the thread-like part of a cell that transmits electrical signals between cells.

The study revealed that these synapses play a central role in the production of this myelin.

“This is the first investigation of these synapses in living tissue,” said lead author Kelly Monk, Ph.D., professor and co-director of the Vollum Institute at OHSU. “This allows us to understand the fundamental properties of how these cells function during normal development. In the future, we may examine how they function differently in the context of MS patients.”

The fact that these synapses exist was the subject of a historic discovery by OHSU researchers at Vollum, published in the journal Nature in May 2000. Until then, it was known that synapses in the brain only transport neurotransmitters between neurons. The discovery of a synapse between neurons and OPCs was therefore a revelation.

“After two decades, we still didn’t know what these synapses did,” Monk said.

Scientists solved the problem using single-cell imaging of living tissue in zebrafish, whose transparent bodies allow researchers to see the inner workings of their central nervous system in real time. Using powerful new tools in imaging, pharmacology and gene editing, researchers were able to use neuron-OPC synapses to predict the timing and location of myelin formation.

The findings likely represent just the tip of the iceberg in terms of understanding the importance of these synapses, said lead author Jiaxing Li, Ph.D., a postdoctoral researcher in Monk’s lab.

Oligodendrocyte precursor cells make up about 5% of all brain cells, meaning the synapses they form with neurons could be relevant in many diseases, including the formation of cancerous tumors.

Li noted that previous studies have suggested a role for OPCs in a range of neurodegenerative diseases, including demyelinating disorders such as MS, neurodegenerative diseases such as Alzheimer’s disease, and even psychiatric disorders such as schizophrenia.

By demonstrating the basic function of the synapse between neurons and OPCs, Li said the study could lead to new methods of regulating OPC function to modify disease progression. For example, these synapses could be key to promoting remyelination in conditions such as MS, where myelin has been degraded. In MS, this breakdown can slow or block electrical signals needed for vision, muscle movement, sensation and thinking.

“There may be a way to intervene to increase the myelin sheath,” he said.

Monk said the finding could be directly relevant to cancer.

“In glioma, these synapses are hijacked to promote tumor progression,” she said. “It might be possible to modulate the synaptic input involved in tumor formation, while still allowing normal synaptic signaling.”

Although these precursor cells represent approximately 5% of all human brain cells, only a fraction forms oligodendrocytes.

“It is becoming clear that these OPCs have functions other than oligodendrocyte formation,” Monk said. “From an evolutionary point of view, it doesn’t make sense to have so many of these precursor cells in your brain if they don’t do anything.”

Their synaptic connection to neurons therefore likely plays a fundamental role in the brain and is worth exploring in the future, she said.

In addition to Monk and Li, co-authors include Tania Miramontes of OHSU and Tim Czopka, Ph.D., of the Center for Clinical Brain Sciences at the University of Edinburgh in the United Kingdom.