Our overarching interest is in the question of how experience and deprivation modify synaptic connections in the brain. Experience-dependent synaptic plasticity is the physical substrate of memory, sculpts connections during postnatal development to determine the capabilities and limitations of brain functions, is responsible for the reorganization of the brain after damage, and is vulnerable in numerous psychiatric and neurological diseases and contributes to their symptoms.
Historically, our major efforts to address this question have been focused on the visual cortex and hippocampus. The visual cortex is a site of robust experience-dependent synaptic plasticity, exemplified by the consequences of temporary monocular deprivation (MD) during childhood. MD sets in motion a stereotyped choreography of synaptic modification whereby the deprived-eye inputs to visual cortex rapidly lose strength and, with a delay, the open-eye inputs undergo a compensatory gain in strength. The behavioral consequence of this plasticity is severe visual impairment in the deprived eye. In humans, this condition is called amblyopia, responsible for loss of vision in over 1% of the world population. Thus, the visual cortex is an excellent preparation to connect the elementary molecular mechanisms of synaptic plasticity to their behavioral consequences. Further, insights into how synapses depress or potentiate have potential clinical applications for the treatment of amblyopia.
The hippocampus is a cortical structure that is critical to forms of learning and memory. The simple cellular architecture of the hippocampus also makes it amenable to electrophysiological investigations of synaptic plasticity that are much more difficult in other parts of the brain. In the early 1990’s we applied insights gained from a theoretical analysis of synaptic plasticity to establish a phenomenon called homosynaptic long-term depression (LTD). LTD is the functional inverse of long-term synaptic potentiation (LTP). Although LTD and LTP are expressed at synapses throughout the brain, they are particularly robust at the Schaffer collateral synapses in the CA1 region of hippocampus. The hippocampus is therefore an excellent preparation to dissect the molecular basis of bidirectional synaptic plasticity. Insights gained here can not only be applied to synaptic modifications elsewhere in the brain, they are also relevant to understanding the basis of hippocampus-dependent memory storage and diseases of cognition.
In the course of studying LTD we made a discovery that has turned out to have major therapeutic significance for human developmental brain disorders that cause autism. One form of hippocampal LTD is triggered by activation of metabotropic glutamate receptor 5 (mGluR5) and requires immediate translation of mRNAs at synapses. In the course of studying this type of synaptic plasticity, we discovered that protein synthesis (and LTD) downstream of mGluR5 is exaggerated in the mouse model of fragile X (FX). Human FX is caused by the silencing of the FMR1 gene, and is the most common inherited form of intellectual disability and autism. Insight gained by the study of LTD suggested that exaggerated protein synthesis downstream of mGluR5 might be pathogenic, and contribute to many symptoms of the disease. Subsequent tests of the “mGluR theory” have shown that inhibition of mGluR5 can correct multiple mutant phenotypes in animal models of fragile X ranging from mouse to fruit fly. Human clinical trials were initiated based on the strength of this science, and results to date indicate that treatments can be developed to substantially benefit this patient population. The mGluR theory has contributed to a major paradigm shift that genetic diseases of brain development, historically viewed as untreatable, may be ameliorated or corrected with appropriate therapy.
Current work in the laboratory is focused on two related themes: (1) mechanisms and regulation of naturally occurring synaptic plasticity in visual cortex, and (2) pathophysiology of genetically defined developmental brain disorders. We primarily study mouse models, and we use a broad range of methods that include but are not limited to brain slice electrophysiology and biochemistry, in vivo electrophysiology and 2-photon functional and structural imaging, and behavioral analysis. Our lab is “question oriented” rather than “method oriented”. We will apply any technology that is needed to address the questions of greatest interest.
Mark F. Bear received his Ph.D. in neurobiology from Brown University. He took postdoctoral training from Wolf Singer at the Max Planck Institute for Brain Research in Frankfurt, Germany, and from Leon Cooper at Brown. He joined the faculty of the Brown University School of Medicine in 1985 and was named a Howard Hughes Medical Investigator in 1996. At Brown, he was awarded the 2000 Elizabeth H. Leduc Award for teaching excellence in the life sciences, and the Class of 2000 Barrett Hazeltine Citation for teaching excellence. In 2003, he was appointed Picower Professor of Neuroscience at The Picower Institute for Learning and Memory in the Department of Brain and Cognitive Sciences at MIT.
Beckman-Argyros Vision Award 2018
IPSEN Foundation Neuroscience Prize 2015
Ray Fuller Award, American Society for Pharmacology and Experimental Therapeutics, 2012
Award for Outstanding Contributions to the Study of Metabotropic Glutamate Receptors, 7th International mGluR Meeting, Taormina, Italy, 2011
Pioneer Award, FRAXA Research Foundation, 2011
William and Enid Rosen Award for Outstanding Contributions to Understanding Fragile X Syndrome, National Fragile X Foundation, 2006
Brown University Elizabeth H. Leduc Award for Teaching Excellence, 2000
Brown University Class of 2000 Barrett Hazeltine Citation for Teaching Excellence
Fogarty Senior International Fellowship, 1993
Society for Neuroscience Young Investigator Award, 1993
United States Office of Naval Research Young Investigator Award, 1988
Alfred P. Sloan Award, 1987
Hector Jose De Jesus-Cortes
Senior Research Scientist
Ingrid Van Welie
Eddie Weng, Ph.D.