A key cellular enzyme called dynamin 1, thought to be essential to all synaptic transmission, is in fact not always necessary for this process, according to researchers at Weill Cornell Medical College and Yale University. Instead, dynamin 1 goes into action only when the synapse enters moments of especially high activity, they report.
"In that sense, dynamin 1 remains crucial, allowing the synapse the freedom to function under all conditions," explains co-senior author Timothy Ryan, Ph.D., professor of biochemistry at Weill Cornell Medical College.
Dynamin 1 is part of a family of enzymes involved in synaptic vesicle endocytosis—a reverse of the process of transmission of cellular signaling chemicals, whereby molecular components of the vesicle are retrieved from the synapse surface and fit back into a new vesicle to be recycled for reuse after the vesicle has discharged its neurotransmitter. One of the steps in this recycling is a biochemical process called fission.
"Early work with the Drosophila fruit fly established dynamin 1's role in this vesicle recycling process," Dr. Ryan notes. "Essentially, the enzyme undergoes a chemical change whereby it physically squeezes off a piece of the old vesicular membrane creating a brand new vesicle poised to take on a new load of neurotransmitter."
Based on this work, neuroscientists had assumed that dynamin 1 was necessary for the growth and function of all synaptic transmission, he continues. Dr. Ryan along with co-senior author Pietro De Camilli, M.D., a Howard Hughes Medical Institute investigator and professor of cell biology at Yale, decided to test that notion. Dr. De Camilli developed a genetically engineered mouse without dynamin 1.
If the enzyme was essential to all synaptic activity, the researchers theorized, these mice would die very soon after birth. But the pups were born, and initially appeared healthy. "That was the really big surprise here," Dr. Ryan says. "Pups lacking dynamin 1 moved and suckled just like normal pups at birth."
Lab study revealed that synaptic activity in these mice was functioning at a low level, enough to keep the mice alive over the short term without dynamin 1. "The enzyme's function appears to be much more subtle than we had imagined," Dr. Ryan explains. "It may not be necessary under conditions of low synaptic activity. In those cases, we suspect that other related enzymes, such as dynamin 2 and 3, may shoulder the load and carry out some residual function.
"But as soon as cells require higher levels of synaptic activity, dynamin 1 becomes absolutely necessary," Dr. Ryan asserts. Normal growth and function demand that neurons work at high capacity, so young mice without dynamin 1 eventually did die off, usually within a week or two of birth.
The researchers published this study in Science.