The Novel Role of Microglia as Modulators of Neurons in the Brain Is Discovered by Mount Sinai Researchers
Findings offer potential target for treating behavioral abnormalities associated with neurodegenerative conditions like Alzheimer’s Disease
Immune cells in the brain that act as scavengers to remove dying cells also play a potentially pivotal role in the regulation of behavior in both mice and humans, a research team from Mount Sinai has found. The newly identified function of the scavenger cells, known as microglia, to protect the brain from abnormal activation in health and disease has implications for treating behavioral abnormalities associated with neurodegenerative and inflammatory diseases in humans. The study was published September 30 in Nature.
“When we think about brain function, we typically think about how neurons control our thoughts and behavior,” says Anne Schaefer, MD, PhD, Professor of Neuroscience, and Psychiatry, at the Icahn School of Medicine at Mount Sinai, and senior author of the study. “But the brain also contains large amounts of non-neuronal cells, including microglia, and our study puts a fresh spotlight on these cells as partners of neurons in the regulation of neuronal activity and behavior. We found that microglia can sense and respond to neuronal activation and provide negative feedback on excessive neuronal activity. This novel microglia-mediated mechanism of neuromodulation could play an important role in protecting the brain from disease.”
Mount Sinai researchers identified the biochemical circuit that supports neuron-microglia communication. When neurons are active, they release a molecule called adenosine triphosphate (ATP). Microglia can sense extracellular ATP, and the compound draws them toward the active neurons. As the next step, the microglia break ATP down to generate adenosine, which then acts on adenosine receptors on the surface of active neurons to suppress their activity and prevent excessive activation.
“In inflammatory conditions and neurodegenerative diseases like Alzheimer’s, microglia become activated and lose their ability to sense ATP and to generate adenosine,” says Ana Badimon, PhD, a former student in the Schaefer Lab and first author of the study.
“This suggested to us that behavioral alterations associated with disease may be mediated, in part, by changes in microglial-neuron communication,” adds Dr. Schaefer, who is also Co-Director of the Center for Glial Biology at The Friedman Brain Institute at the Icahn School of Medicine.
Dr. Schaefer describes the identification of the biochemical circuit that enables microglial control of neuronal responses as a potential “paradigm shift” in our understanding of how innate immune cells in the brain can contribute to behavior. This observation is particularly important, she adds, given the fact that microglia, while residing in the brain, are uniquely equipped to also respond to signals generated in the peripheral body. Microglia can therefore act as an interface between peripheral body changes, like a viral infection, and the brain by communicating these signals to neurons to modulate behavioral responses.
By shedding valuable light on the interaction of neurons and microglia, the study carries a number of practical implications for further research. They range from novel approaches of neuromodulation of normal behaviors by targeting microglia, to potential treatment of behavioral abnormalities associated with neurodegenerative diseases.
“The future promise of our study also lies in the identification of novel signals like ATP that will allow microglia to modulate the function of highly diverse neurons, including neurons controlling sleep or metabolism,” says Dr. Schaefer. “We believe our work has the potential to add to our knowledge about the mechanisms of neuromodulation.”
Other partners in the Mount Sinai-led study include California Institute of Technology, the Nagoya University Graduate School of Medicine in Japan, Kobe University Graduate School of Medicine in Japan, University of Minnesota, and Harvard Medical School.
The research described in this press release is funded in part by the National Institutes of Health, The Brain and Behavior Research Foundation, The Whitehall Foundation, and The Edward Mallinckrodt Jr. Foundation.
The National Institute on Aging, part of the National Institutes of Health, recently awarded the Icahn School of Medicine at Mount Sinai a $2.99 million grant (number RF1AG068558) that will enable Dr. Schaefer and colleagues to investigate the epigenetic mechanisms of systems microglia activation during aging and its contributions to neurodegenerative diseases.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties.