Dr. Mark Bear

Picower Professor of Neuroscience
Howard Hughes Medical Institute (HHMI) Investigator
Co-Founder, Allos Pharma Inc.

Primary DLC

Department of Brain and Cognitive Sciences

MIT Room: 46-3301

Areas of Interest and Expertise

Fragile X
Cortical Neurons

Research Summary

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.

Recent Work