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Twitching synapses provide new insight into brain development

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Tissue plasminogen activator (tPA), a common brain chemical that is used to dissolve blood clots in the brain after a stroke, can hasten the structural remodeling of synapses, neuroscientists at the Picower Center for Learning and Memory at MIT report in the Dec. 16 issue of Neuron.

Mriganka Sur, the Sherman Fairchild Professor of Neuroscience at the Picower Center, and colleagues looked at how the structure of single dendritic spines--the location of single synapses--changes when inputs to the visual cortex change during a critical window of development. Synapses start to change as little as two days after one eye is deprived of sight. This work builds on a groundbreaking experiment in the 1960s that showed that if one of an animal's eyes was closed during early brain development and later re-opened, it never regained normal function. Synapses associated with the closed eye started to respond to the open eye instead.

For the first time, the researchers show that this structural plasticity is likely to be mediated by enzymes that degrade the extracellular matrix, creating a flexible environment for structural rearrangement. Understanding the role of molecules like tPA in promoting plasticity in the adult brain may lead to future interventions that would enhance learning and memory, said Sur, who is head of MIT's Department of Brain and Cognitive Sciences (BCS).

"Most previous work in this field had focused on the role of intracellular signals, or processes activated inside cells by the level of electrical drive at synapses, as key to understanding changes in synaptic function and structure," Sur said. "Our work underscores the importance of linking intracellular processes with extracellular mechanisms, or processes that exist outside of the cell but are nonetheless influenced by electrical activity. It opens up a large area of future work on the role of tPA and similar molecules that influence the extracellular matrix during plasticity of connections."

This work focuses on dendritic spines--mushroom-shaped structures that protrude from a tip of a branch of the tree-shaped dendrite-part of the neuron. A dendritic spine forms one-half of a synapse. The dendrites of cortical neurons are densely covered with spines that enable single cells to receive input from thousands of others, leading to the changes in dendritic spine shape and density that underlie learning and memory.

When the connection between two neurons is strengthened by repeated sensory input, the ability of the presynaptic cell to activate the postsynaptic cell is enhanced. This forms the basis of synaptic plasticity.

Serkan Oray, a graduate student in BCS and at the Picower Center, and postdoctoral fellow Ania Majewska measured the structure of single dendritic spines using a technique called two-photon microscopy, which allows researchers to visualize tiny cell structures in the living animal. Before electron microscopy showed dendritic spines to be real structures, no one was sure they existed. Each spine is less than a micron in width, about a hundredth the width of a human hair, and there are trillions of them in the human brain.

Spines change in shape and size as synapses change in function. Understanding how synapses and spines are altered is central to understanding how connections between brain cells form as the cortex develops, which is key to understanding how the environment shapes brain networks during development.

Oray and Majewska found that individual spines "twitch," or change in size with time, during the period connections are forming. The less electrical drive on a spine, the more it twitches. "Depriving the cortex of vision briefly increases the twitching, likely as a prelude to the spine, and the synapse, disappearing or reorganizing its connections," Sur said. The twitching is highest in the superficial and deep layers of cortex--the layers that are affected the fastest by visual deprivation.

The researchers were intrigued to find that a mechanism that controls the twitching is the extracellular matrix, or the glue of large sugar molecules that holds cells together. Degrading the extracellular matrix by adding tPA, an enzyme administered immediately following a stroke to dissolve blood clots, increases the twitching. "This experiment provides powerful evidence that tPA is active during plasticity of visual connections," Sur said.

MIT President Susan Hockfield, a neuroscientist, had proposed in earlier work at Yale that degrading or dissolving the extracellular matrix may be important for promoting changes in the structure of neurons and connections.

This work is supported by a Whiteman Fellowship and the National Institutes of Health.

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