A research team led by Michael Fox, a professor at the Fralin Biomedical Research Institute at VTC, has identified the type of brain cell that produces collagen 19, a protein that is crucial for the formation of inhibitory circuits in the brain.
The study, published in the Journal of Neuroscience, depicts a previously unknown molecular mechanism underlying healthy brain development.
Neurons and glia are the most abundant types of brain cells. Glia, in particular star-shaped glia called astrocytes, release molecules that support the growth and maintenance of healthy synapses, the chemical communication structures between neurons and their targets including other neurons. Yet in this study, Fox’s team discovered that a type of neuron called an interneuron, a cell type that processes information, produces the majority of brain-derived collagen 19 to stimulate synapse formation.
“At a time when many studies are identifying interneuron-like roles for astrocytes, we’ve identified an unexpected astrocyte-like role for interneurons,” said Fox, who is also the director of the School of Neuroscience in Virginia Tech’s College of Science.
In previous research, Fox’s team discovered that mice lacking the gene that encodes collagen 19 exhibit a loss of inhibitory synapses surrounding neuronal cell bodies located in the brain’s hippocampus and neocortex. In humans, these brain regions are involved in cognitive functions, such as reasoning, language, perception, memory and learning. In mice, these regions have been shown to be involved in sensory perception, learning and memory.
Fox’s earlier discovery about the importance of collagen 19 beckoned another question: Where does this protein come from?
In the new study, the scientists used riboprobes – small segments of ribonucleic acids (RNA) that bind to complementary segments of RNA – to look for different cell type markers in normal mice, wild-type and mice with the genetic mutation. This method revealed that the majority of brain-derived collagen 19 is produced by a type of interneuron.
“Initially when we proposed this, some people thought it was far-fetched that one neuron could influence another cell’s development when they’re not synaptically coupled,” Fox said.
Roughly 20 percent of a person’s body mass is made of collagens, which form the matrix of connective tissue that wraps around organs, muscles and cellular structures. Because of the complex molecular structure of collagens, just a small genetic variation alters the protein’s shape, rendering the collagen molecule useless waste that cells destroy and recycle for parts.
Collagen genetic mutations are linked to a litany of connective tissue disorders, but Fox says they’re still underexplored in the brain.
Fox’s lab plans to build on this discovery by working to develop new ways to restimulate inhibitory synapse growth in diseased or injured brains. The team previously found that a small peptide derived from this collagen, matricyptin, is sufficient to promote the growth of inhibitory synapses in cells lacking collagen 19.
“We want to translate what we’re learning about how these circuits develop into therapeutics,” Fox said. “We’ve found a peptide that shows some promise in stimulating inhibitory synapse formation and are studying ways to employ it.”