The nervous system works because neurons communicate across connections called synapses. They “talk” when calcium ions flow through channels into “active zones” that are loaded with vesicles carrying molecular messages. The electrically charged calcium causes vesicles to “fuse” to the outer membrane of presynaptic neurons, releasing their communicative chemical cargo to the postsynaptic cell. In a new study, scientists at The Picower Institute for Learning and Memory at MIT provide several revelations about how neurons set up and sustain this vital infrastructure.

“Calcium channels are the major determinant of calcium influx, which then triggers vesicle fusion, so it is a critical component of the engine on the presynaptic side that converts electrical signals to chemical synaptic transmission,” said Troy Littleton, senior author of the new study in eLife and Menicon Professor of Neuroscience in MIT’s Departments of Biology and Brain and Cognitive Sciences. “How they accumulate at active zones was really unclear. Our study reveals clues into how active zones accumulate and regulate the abundance of calcium channels.”

Neuroscientists have wanted these clues. One reason is that understanding this process can help reveal how neurons change how they communicate, an ability called “plasticity” that underlies learning and memory and other important brain functions. Another is that drugs such as gabapentin, which treats conditions as diverse as epilepsy, anxiety and nerve pain, binds a protein called alpha2delta that is closely associated with calcium channels. By revealing more about alpha2delta’s exact function, the study better explains what those treatments affect.

The more scientists knocked out a protein called alpha2delta with different manipulations (right two columns), the less Cac calcium channel accrued in synaptic active zones of a fly neuron (brightness and number of green dots) compared to unaltered controls (left column).

“Modulation of the function of presynaptic calcium channels is known to have very important clinical effects,” Littleton said. “Understanding the baseline of how these channels are regulated is really important.”

MIT postdoc Karen Cunningham led the study, which was her doctoral thesis work in Littleton’s lab. Using the model system of fruit fly motor neurons, she employed a wide variety of techniques and experiments to show for the first time the step by step process that accounts for the distribution and upkeep of calcium channels at active zones.

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