The strength of connections between neurons in the brain, a property called synaptic plasticity, plays a central role in learning, the formation of memories, and the processes through which our brain pieces together countless streams of information.
Matthew J. Kennedy, Ph.D., of the University of Colorado Denver School of Medicine, has been using his 2011 NARSAD Young Investigator Grant to conduct research to better understand the factors that influence synaptic plasticity, and how these are disrupted in a range of brain and behavior disorders ranging from schizophrenia and autism to addiction and Alzheimer’s disease.
In the May 13th issue of the Journal of Cell Biology, Dr. Kennedy and colleagues reported to the research community that they had invented and demonstrated a new method of manipulating brain cells in order to carry out such studies. Their new technology, a protein secretion system, enables them to perform research that is impossible to do with existing technologies, or is impractical or too costly to do.
The research team has devised a new way of controlling interactions among proteins―a method that enables them to use light to trigger protein secretion. Secretion is a fundamental biological process that in nerve cells in the brain is involved in “trafficking” protein “cargoes” from holding areas to other parts of the cell where they are needed―for instance, in building connections between neurons.
The insight that enabled Dr. Kennedy and colleagues to develop the technology was to fuse a light-sensitive protein found in plants, called UVR8, with proteins of interest in a cell staging and storage area called the endoplasmic reticulum, or ER. When such proteins were exposed to a kind of ultraviolet light called UV-B, they began moving toward the cell’s membrane. Because light is the trigger for cargo to leave the ER, this technology offers the potential for exquisite temporal and spatial control of secretion. When tested in neurons, the method enabled the team to control trafficking of the proteins to so-called “dendritic branch points,” or junctions where the threadlike projections from nerve cell bodies reach out to find other neurons. The dendrites are the nerve cell’s “output channels.” Thus, this technology will allow users to control and track how proteins responsible for making and shaping synaptic connections move from holding areas like the ER to synapses.
“Understanding the basic mechanisms of synaptic function, and how synapses are perturbed in neuropsychiatric illnesses, will be critical for developing future therapeutic strategies,” says Dr. Kennedy. “One fundamental synaptic function is the remarkable ability of synapses to change in response to experience (synaptic plasticity). Because this process is disrupted in many different disorders, the mechanisms governing plasticity could be good targets for therapeutic intervention.”
Dr. Kennedy says the initial NARSAD Grant funding enabled him to gather critical preliminary data for numerous further awards, including a five-year NIH Grant.
Read an abstract of this research paper.