The nervous system is remarkably flexible in dealing with information across different timescales. We can react to emergencies in milliseconds, yet also store treasured memories for years. How the nervous systems navigates information with various timing demands is a major question in the field of neuroscience.
One of the strategies the nervous system uses to meet these timing challenges is to transmit information in two different ways. Electrical signals give the nervous system speed. Chemical signals give it flexibility to modulate signals across time. These two signals interface at the synapse.
The synapse is the location where one neuron connects to another. When a neuron “fires”, it is transmitting a fast electrical signal down its axon to the synapse at the axon terminal. At the synapse, the fast electrical signal is converted into a slow chemical signal. Neurotransmitters (such as glutamate or dopamine) wait at the axon terminal, where they are packaged into vesicles. When the electrical signal reaches the synapse, the vesicles are triggered to fuse with the membrane and release their contents into the synapse. The neurotransmitter subsequently binds to receptors on the surface of the receiving neuron – effectively transmitting information from one neuron to another. Critically, the chemical signaling is an opportunity for the nervous system to modulate the information being transmitted, such as by switching the amount or type of neurotransmitter available. In 2013, the Nobel Prize in physiology and medicine was awarded to three scientists who discovered the molecular details of how neurons release their packaged vesicles of neurotransmitter.
Dr. Erik Jorgensen is interested in what happens as the neuron begins to use up its available packages. The stock of packages is finite and most neurons fire quickly enough to use up their stores in a matter of seconds. It is thought that neurons are somehow able to quickly recycle their packages to counter act this problem, but evidence to support this idea has been scant. Vesicles are too small to observe with a light microscope and neurons fire in about ten milliseconds. Being able to see what is occurring at the synapse over such a short timescale is a difficult task.
To address this question, Jorgensen worked with Dr. Shigeki Watanabe to develop a new technique which gave them the proper temporal and spatial resolution to understand how the neurotransmitter packages were being replenished. First, they introduced a light sensitive molecule to neurons – by turning on and off a light the researchers were able to precisely control when the neuron fired. Then, they would use a high pressure freezer, which could lock all vesicles in place within eight milliseconds. By freezing neurons at different time points, they could effectively create a time-lapse of what the vesicles were doing. Finally, by examining these snapshots of vesicles with an electron microscope, they had the spatial resolving power to examine the vesicles in detail.
Watanabe and Jorgensen found that the vesicles completely fused with the neuron membrane within 30 milliseconds, allowing the vesicles to dump out their neurotransmitter payload into the synapse. Remarkably, in less than 100 milliseconds, portions of the membrane began retracting to be recycled into new vesicles. This ultra-fast recycling process of vesicles was previously unknown. A slower recycling method was known to take place in some cells, but this mechanism occurred too slowly to meet the demands of neurons. Jorgensen is now following up on this work to discover the details of how neurons are able to perform this ultra-fast feat.
If you are interested in the details of this work, Katie Fife will be presenting the paper at journal club this Monday, April 20th at 5:30PM in Pacific Hall 3502.
Additionally, Dr. Erik Jorgensen will be giving a talk on this topic titled “Ultrafast endocytosis of synaptic vesicles” this Tuesday, April 21st at 4:00PM for the Neurosciences Graduate Program Dart NeuroScience Seminar Series. The talk is at the Center for Neural Circuits and Behavior (CNCB).
Watanabe S, Rost BR, Camacho-Pérez M, et al. Ultrafast endocytosis at mouse hippocampal synapses. Nature. 2013;504(7479):242-247. doi:10.1038/nature12809.
Peter Osseward is a first-year student in the Neurosciences PhD program at UCSD. He is currently rotating with Dr. Xin Jin. In his spare time, Peter likes to hike and play Ultimate Frisbee.