New research from Oregon Health & Science University on synapses reveals for the first time the function of a little-understood junction between brain cells that could have important therapeutic implications for conditions ranging from multiple sclerosis to Alzheimer's disease to a type of brain cancer known as glioma.
The results of the study were published in Nature Neuroscience
Study of the complexity of synapses: here's what the new research says
Neuroscientists have focused on the junction, or synapse, that connects neurons to a non-neuronal cell, known as oligodendrocyte precursor cells, or OPCs. OPCs can differentiate into oligodendrocytes, which produce a sheath around the nerves known as myelin. Myelin is the protective sheath that covers the axon of each nerve cell, the thread-like portion of a cell that transmits electrical signals between cells.
The study found that these synapses play a critical role in myelin production: “This is the first investigation of these synapses in live tissue,” said senior author Kelly Monk, Ph.D., professor and co-director of the Vollum Institute at OHSU. “This provides an understanding of the basic and fundamental properties of how these cells function during normal development. In the future, we may examine how they work differently in the context of MS patients.”
The fact that these junctions exist was the subject of a landmark discovery by OHSU Vollum researchers, published in the journal Nature in May 2000. Until that time, junctions in the brain had been known to transport neurotransmitters between neurons, so the discovery of a synapse between neurons and OPCs was a revelation.
“After two decades, we still didn't know what these synapses did,” Monk said. The scientists tackled the problem using single-cell imaging of live zebrafish tissue, whose transparent bodies allow researchers to see the inner workings of their central nervous system in real time.
Using powerful new imaging, pharmacology and gene editing tools, researchers were able to use neuron-OPC synapses to predict the timing and location of myelin formation.
The findings are likely the tip of the iceberg in terms of understanding the importance of these junctions, said lead author Jiaxing Li, Ph.D., a postdoctoral researcher in Monk's lab.
Oligodendrocyte precursor cells comprise approximately 5% of all brain cells, meaning that the synapses they form with neurons could be relevant to many pathological conditions, including the formation of cancerous tumors.
Li noted that previous studies have suggested a role for OPCs in a number of neurodegenerative conditions, including demyelinating disorders such as multiple sclerosis, neurodegenerative diseases such as Alzheimer's, 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 alter disease progression.
For example, these synapses could be key to promoting remyelination in conditions such as MS, in which myelin has been degraded. In MS, this degradation can slow or block the electrical signals needed for people to see, move muscles, feel sensations and think.
“There may be a way to intervene so we can increase the myelin sheath.” Monk said the finding could be immediately relevant to cancer.
“In glioma, these synapses are hijacked to drive tumor progression,” he said. “It may be possible to modulate the synaptic input involved in tumor formation while still allowing normal synaptic signaling.”
Although these precursor cells make up about 5% of all human brain cells, only a fraction goes on to form oligodendrocytes.
“It's becoming quite clear that these OPCs have other functions beyond forming oligodendrocytes,” Monk said. “From an evolutionary perspective, it doesn't make sense to have so many of these precursor cells in the brain if they're not doing something.”
Their synaptic connection to neurons therefore likely plays a critical role in the brain and deserves to be explored in the future, he said.
Further research is reshaping our understanding of the brain's fundamental building blocks, the proteins found in synapses. Titled “The proteomic landscape of synaptic diversity across brain regions and cell types,” the research delves into the intricate world of synapses, the vital connections between neurons.
Synapses are the connections between neurons that allow them to communicate with each other. In all cells, including neurons, protein molecules are the main players that carry out cellular work. Synapses are made up of thousands of proteins, each of which plays a unique role in brain function.
Brain junctions have different functions – from pacemaker-like activity to drive brain rhythms to pulsatile properties – and release different chemicals, “neurotransmitters” and modulators. All proteins expressed in a cell or its compartment are called the “proteome”.
< p>In the study, the researchers answered a fundamental question: What are the specific proteomes that define different types of brain junctions?
Scientists have long known that there are different types of synapses, but the specific protein combinations responsible for their diversity have remained a mystery. Understanding the different protein combinations that drive the function of different junctions is critical to deciphering brain function and also what goes wrong during disease.
To answer the question of which specific proteomes define different types of synapses, Schuman's team first isolated the synapses of different types of neurons in different areas of the brain. They used genetically modified mice in which the synapses of interest were fluorescently labeled, allowing their isolation and purification.
Using quantitative mass spectrometry, a method that allows the levels of individual proteins to be identified and quantified, van Oostrum et al. they analyzed 18 different types of junctions in five different brain regions.
The research uncovered common synaptic protein modules that exist in most junctions, but also uncovered specific “proteomic hot spots” that drive the specialized function of synapses. For example, in a class of junctions that release the neurotransmitter dopamine, there was a specific depletion of a molecule that helps cells deal with oxidative stress. Schuman says, “We are intrigued by this finding, given the vulnerability of dopaminergic junctions to oxidative stress and their loss during Parkinson's disease.”
These findings not only provide valuable insights into fundamental principles of brain function, but also open new avenues for research and potential human therapies. Subsequent studies could explore targeted therapeutic interventions, which could lead to treatments for neurological disorders rooted in synaptic dysfunction.
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