studies featuring research from Weill Cornell Medical College have
uncovered surprising details about the complex process that leads to the
flow of neurotransmitters between brain neurons—a dance of chemical
messages so delicate that missteps often lead to neurological
recent Nature Neuroscience study led by Dr. Timothy Ryan, professor of
biochemistry at Weill Cornell Medical College, demonstrates that
individual neurons somehow control the speed by which they recycle
synaptic vesicles that store neurotransmitters before they are released.
No one had expected that neurons would have such a powerful “gas
pedal,” says Dr. Ryan.
Ryan is also contributing author of a second, Yale Univ.–led study
published in an online edition of Neuron. It shows that the
common understanding about how proteins help form these key storage
vesicles is flawed.
two findings help refine science’s understanding of the biomechanics
that control neurotransmission at the synaptic gap between brain
neurons, Ryan says.
are looking under the hood of these machines for the first time,” he
says. “Many neurological diseases such as Alzheimer’s disease,
Parkinson’s disease, schizophrenia, and other neurodegenerative and
psychiatric disorders are considered to be synaptopathies—pathologies
of synaptic function. So repairing them will require that we understand
how they work.”
studies focus on synaptic vesicles, which are bubble-like structures
that store neurotransmitters within a bi-layer of fatty membranes at the
know that in order to deliver neurotransmitter messages between cells,
the synaptic vesicle merges with the surface of the brain cell at the
synapse and releases the message. Then these synaptic vesicles, which
are in limited supply, must be retrieved, rebuilt and refilled with
neurotransmitters, Ryan says. “Failure to do so would result in the
synapse running out of vesicles rather quickly, and proper
neurotransmitter function depends on their continuous availability.”
Measuring neuronal speed
Nature Neuroscience study was designed to look at what controlled the
speed of the vesicle recovery process. This speed, which dictates the
availability of vesicles, has long been considered to be one of the
limits as to how fast neurons can continuously communicate, especially
in high-demand situations, Dr. Ryan says.
study the speed of this recovery process, senior author Ryan and
first author Moritz Armbruster, a Rockefeller Univ. graduate
student who worked in Dr. Ryan’s laboratory, used a tool that took
optical recordings of the speed of vesicle recycling across 84 different
discovered something quite unexpected—an individual neuron retrieves
all of its synaptic vesicles at pretty much the same speed.
is as if the neuron is following orders from a cell-wide central gas
pedal,” Dr. Ryan says. They also found that while each cell had its own
speed at recovering the vesicles, that rate varied four-fold across the
different neurons—even if the neurons were performing identical
functions, such as secreting the same neurotransmitter.
we compared different neurons, we found that each cell is telling its
synapses to go at its own speed,” he says. “The mystery that remains is
the nature of this gas pedal, and if it might be important in
therapeutic approaches to tackling synaptopathies.”
Debunking the dynamin theory of synaptic recovery
Neuron study looked at proteins involved in one phase of the recovery
process, the separating and pinching off of the membrane of the synaptic
vesicle from the membrane of the neuronal cell. It was led by Dr.
Pietro De Camilli, a professor of cell biology and neurobiology at Yale
Univ. and a Howard Hughes Medical Institute investigator, and his
colleague Dr. Shawn Ferguson, currently an assistant professor of cell
biology also at Yale.
on studies in the 1980s, researchers had believed that a protein called
dynamin, which comes in three forms (1, 2, and 3), was critical to this
“membrane fission” step in the formation of vesicles.
2007, the Yale researchers tested whether dynamin 1, which represents
90% of all dynamin in the brain, was, as believed, the key
protein involved in synaptic vesicle membrane fission. They generated a
mouse that lacked the protein but found it produced only subtle
differences in the fission process. This surprising discovery was
published in Science.
the new study, the research team, which included Ryan, Armbruster and others, looked at what happened when both dynamin 1 and
dynamin 3, which makes up 99% of dynamin protein, are missing.
They used the same optical methods employed in the Nature Neuroscience
study to examine the speed of the synaptic vesicle retrieval process.
studies showed that retrieval is now severely impaired when you have
neither dynamin 1 nor dynamin 3, which shows us that dynamin 3 has a
major presynaptic function,” Ryan says. “Remarkably, however, the
retrieval process still happens, and it is unknown whether that could be
due to dynamin 2, because that protein accounts for only a tiny
percentage of dynamin protein in the brain. It makes sense that there is
another protein or biomechanical process that is contributing.”
is a protein known to play a critical role in synaptic vesicle
retrieval. The observation that synaptic transmission can still occur,
albeit in a much-impaired way, in the absence of the overwhelming
majority of dynamin reveals a remarkable and unexpected plasticity of
nerve terminals, says Dr. De Camilli.
Nature Neuroscience study was funded by grants from the National
Institutes of Health and the David Rockefeller Graduate Study of the
Neuron study was supported in part by the G. Harold and Leila Y.
Mathers Charitable Foundation, National Institutes of Health grants, and
the W.M. Keck Foundation. Co-authors are, from Yale Univ. School
of Medicine: Andrea Raimondi, Shawn M. Ferguson, Xuelin Lou, Summer
Paradise, Silvia Giovedi, Mirko Messa, Nao Kono, Junko Takasaki,
Valentina Cappello; and Eileen O’Toole from the Univ. of Colorado