Protein underlies brain’s response to activity

Experience helps shape the brain, but how that happens – how synapses are remodeled in response to activity – is one of neurobiology’s biggest mysteries. Though axons and dendrites can be easily spotted waxing and waning under the microscope, the molecular middlemen working inside the cell to shape the neuron’s sinewy processes have been much more elusive.

Two independent teams of Harvard Medical School (HMS) researchers report that they have found a protein that either pares down or promotes a neuron’s synapses, depending on whether or not the neuron is being activated. Rather than work at the far reaches of the cell, in the axon or dendrite, the protein myocyte enhancer factor 2 (MEF2) resides in the nucleus, where it turns on and off genes that control dendritic remodeling. In fact, the researchers have identified some of MEF2’s targets. In addition, one of the teams has identified how MEF2 switches from one program to the other, that is, from dendrite- promoting to dendrite-pruning. The discoveries are reported in back-to-back papers in the Feb. 17, 2006 Science.

The uncovering of the MEF2 pathway and its genetic switch helps fill in a theoretical blank in neurobiology, but what excites the researchers are the potential implications for the clinic. “Changes in the morphology of synapses could turn out to be very important in a whole host of diseases including neurodegenerative as well as psychiatric disorders,” said Azad Bonni, HMS associate professor of pathology, who, with research fellow Aryaman Shalizi, HST medical student Brice Gaudilliére, and colleagues, authored one of the papers. Graduate student Steven Flavell and Michael Greenberg, HMS professor of neurology at Children’s Hospital Boston, who led the other team, believe that the MEF2 pathway could play a role in autism and other neurodevelopmental diseases.