Columbia University scientists have developed a new optical technique to study how information is transmitted in the brains of mice. Using this method, they found that only a small portion of synapses—the connections between cells that control brain activity—may be active at any given time.
The study was published in the latest issue of Nature Neuroscience.
“Understanding how we accomplish complex tasks, such as learning and memory, requires us to look at how our brains transmit key signals—called neurotransmitters—across synapses from one neuron to another,” said David Sulzer, PhD, professor of neurobiology in Psychiatry, Neurology, and Pharmacology at Columbia University Medical Center (CUMC). “Older techniques only revealed what was going on in large groups of synapses. We needed a way to observe the neurotransmitter activity of individual synapses, to help us better understand their intricate behavior.”
To obtain a detailed view of synaptic activity, Sulzer’s team collaborated with the laboratory of Dalibor Sames, PhD, associate professor of chemistry at Columbia, to develop a novel compound called fluorescent false neurotransmitter 200 (FFN200). When added to brain tissue or nerve cells from mice, FFN200 mimics the brain’s natural neurotransmitters and allows researchers to spy on chemical messaging in action.
Using a fluorescence microscope, the researchers were able to view the release and reuptake of dopamine—a neurotransmitter involved in motor learning, habit formation, and reward-seeking behavior—in individual synapses. When all the neurons were electrically stimulated in a sample of brain tissue, the researchers expected all the synapses to release dopamine. Instead, they found that less than 20 percent of dopaminergic synapses were active following a pulse of electricity.
“Why are there these large reservoirs of synapses that are silent?” said Dr. Sames, a co-author of the paper. “Perhaps these silent terminals hint at a mechanism of information coding in the brain that’s yet to be revealed.”
The study’s authors plan to pursue this hypothesis in future experiments, as well as examine how other neurotransmitters behave.
“This particular study didn’t explain what’s causing most of the synapses to remain silent,” said Dr. Sulzer. “If we can work this out, we may learn a lot more about how alterations in dopamine levels are involved in brain disorders such as Parkinson’s disease, addiction, and schizophrenia.”
The study is titled, “Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum.” The other contributors are: Daniela B. Pereira, Yvonne Schmitz, Josef Meszaros, Paolomi Merchant, Gang Hu, Shu Li, Adam Henke, Jose E. Lizardi-Ortiz, Richard J. Karpowicz, Jr., Travis J. Morgenstern, Mark S. Sonders, Ellen Kanter, Pamela C. Rodriguez, and Eugene V. Mosharov,.
The study was supported by grants from the G. Harold & Leila Y. Mathers Charitable Foundation, the National Institute of Mental Health (grants R01MH086545 and R01MH108186), the National Institute of Neurological Disorders and Stroke (grant R01NS075222), the National Science Foundation, the JPB, McKnight and Michael J. Fox Foundation, and the Udall Center of Excellence for Parkinson’s Disease Research.
The Parkinson’s Disease Foundation also supported this work.
The authors declare competing financial interests: details are available in the online version of the paper. D. Sulzer and D. Sames were listed as inventors on a patent (8,337,941) covering FFN200 and a patent application (13/575,535) covering FFN102, com- pounds employed in this study.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.