Understanding How Neurons Communicate May Help Treat Brain Disorders
For the first time, Weill Cornell scientists have learned important details illustrating how neuronal cells in the brain communicate at a microcellular level. Such knowledge may help in the development of drug compounds used to treat disorders caused by malfunctions in communication between brain cells, such as schizophrenia, epilepsy, Parkinson’s and Alzheimer’s disease.
To communicate between cells, tiny transport vesicles package and ship neurotransmitter-chemicals to the end (terminals) of the cell and then across synapses, or gaps in-between neurons. Adjacent neurons then receive the signal. To do this, these transport-vesicles must be recycled quickly — especially during boosts in brain activity, but it has never been understood exactly how such critical recycling works.
Observing proteins within cellular vesicles labeled with a fluorescent marker in the lab, for easy identification, the researchers saw that about 20 vesicles can be simultaneously manufactured right at the end of the neuron — like milk bottles, lined up and waiting to be filled for shipment. The new findings show that calcium ions, which help to send the signal across the synapse to another neuron, also control the cell’s ability to rebuild the vesicles at the cell’s terminal end.
According to the researchers, the explanation for this cellular feat is a simple matter of distance. “Think of the cell body as New York City and the axon [the long narrow stretch between the cell body and cell terminal] as a highway leading to Boston,” explains lead researcher, Dr. Tim Ryan, from the Department of Biochemistry at Weill Cornell Medical College.
“It takes far too long for the vesicles to move from all the way in the cell body to another cell. These vesicles are made in New York and slowly transported to the cell’s terminal end, but some are made right in Boston for immediate use.” Dr. Ryan hopes that by understanding the mechanics of the cellular trafficking machine, he and other scientists will ultimately be able to identify and repair numerous neurologic malfunctions.
J Neurosci. 2008 Jun 25;28(26):6742-9.
Calcium control of endocytic capacity at a CNS synapse.
Balaji J, Armbruster M, Ryan TA.
The ability to recycle synaptic vesicles is a crucial property of nerve terminals that allows maintenance of synaptic transmission. Using high-sensitivity optical approaches at hippocampal nerve terminals in dissociated neurons in culture, we show that modulation of endocytosis can be achieved by expansion of the endocytic capacity. Our experiments indicate that the endocytic capacity, the maximum number of synaptic vesicles that can be internalized in parallel at individual synapses, is tightly controlled by intracellular calcium levels. Increasing levels of intracellular calcium, which occurs as firing frequency increases, significantly increases the endocytic capacity. At physiological temperature after 30 Hz firing, these synapses are capable of endocytosing at least approximately 28 vesicles in parallel, each with a time constant of approximately 6 s. This calcium-dependent control of endocytic capacity reveals a potentially useful adaptive response to high-frequency activity to increase endocytic rates under conditions of vesicle pool depletion.