Virginia Tech Carilion Research Institute scientists find molecular clue in development of schizophrenia
The left image is a rodent brain without the protein that helps form inhibitory synapses (shown in green). The right image is a rodent brain treated with a fragment from the protein, and has formed several inhibitory synapses.
Scientists at the Virginia Tech Carilion Research Institute have found that a small protein fragment significantly contributes to the brain’s healthy wiring. They also found that the disruption of the same fragment may lead to the development of schizophrenia.
“Schizophrenia might be caused by a number of factors, including both environmental and genetic factors,” said Michael Fox, an associate professor at the Virginia Tech Carilion Research Institute and an author on the paper. “In this study we discovered that the genetic deletion of collagen XIX leads to symptoms that resemble schizophrenia in a mouse model.”
The researchers recently published their results in The Journal of Cell Biology.
Collagen XIX is an extracellular protein—a protein that exists in the fluid surrounding cells. Previous research in human patients with schizophrenia has pointed to the genetic region that codes for collagen XIX as a possible culprit.
“In this study we sought to answer whether the absence of collagen XIX leads to schizophrenic-like behavior, and, if so, why?” Fox said.
Fox and his team found that rodents without this collagen failed to assemble inhibitory synapses in the brain.
A kind of cellular brake, inhibitory synapses keep excitatory electrical signals from running rampant in the brain. This prevents brain cells from becoming hyperactive, which could lead to hallucinations and delusions, as well as an inability to process emotions or think logically—all symptoms of schizophrenia. More than 3 million people in the United States suffer from this disorder.
“A surprise from these studies was that this collagen is expressed in the brain,” Fox said. “For decades neuroscientists have thought the brain was devoid of collagen.”
Not only is collagen XIX, known as an unconventional collagen, generated in the brain, but it is also made by neurons—the brain cells that build neural circuits. Fox had suspected that the brain contained collagen for nearly a decade, and his preliminary efforts were recognized in 2015 with a NARSAD Independent Investigator award. Now, Fox is beginning to understand the exact mechanisms by which the collagen contributes to brain development.
Collagen XIX can be fragmented into smaller peptides, including a matricryptin. Fox and his team applied the matricryptin to neuronal cells without collagen XIX. As the scientists expected, the cells formed inhibitory synapses.
“We want to learn more about how collagen XIX’s matricryptin promotes the formation of synapses,” Fox said. “We found this small peptide was a potent inducer of inhibitory synapse formation. Based on this result, we will next explore whether the peptide could be used as a possible therapeutic for people with schizophrenia.”
According to Michael Friedlander, the executive director of the Virginia Tech Carilion Research Institute, Fox is carrying out innovative and foundational studies on the development of the internal environment and assembly of the brain.
“Dr. Fox and his research team are using their discoveries to advance our understanding, through animal models, of some of the most devastating neuropsychiatric disorders,” Friedlander said. “We’re very fortunate to have Dr. Fox as a leader in the Virginia Tech Carilion Research Institute neuroscience research program.”
