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VIDEO: In evoked neurotransmission (left), large numbers of vesicles fuse simultaneously, releasing neurotransmitters
that cross the synapse gap and activate multiple receptors — the primary way neurons communicate.
Brain "noise" may nurture synapse growth
Miniature neurotransmissions appear to play a key role in synapse development.
A new study shows us that a long-overlooked form of neuron-to-neuron communication — miniature neurotransmissions — are essential in the development of synapse regions where nerve impulses are transmitted and received. The findings came from work in fruit flies, and raise the possibility that abnormalities in miniature neurotransmissions contribute to neurodevelopmental disease.
The research was done at Columbia University Medical Center (CUMC) and published in the journal Neuron.
The primary way in which neurons communicate with each another is through "evoked neurotransmission." This process begins when an electric signal is sent through the long neural extension called the axon. When this electric signal reaches the synapse gap, it triggers a release of chemicals to jump across that gap and bind with more chemicals which activate receptors on the opposite side of the gap. And, if "motor nerves," muscles are now stimulated to contract.
Neurotransmitter chemicals are packaged into like-sized subcellular packages known as synaptic vesicles when transmitted. Vesicles are released by the hundreds, perhaps thousands, with each transmission. Evoked neurotransmission was first described in the 1950s by Sir Bernard Katz who shared the Nobel Prize in physiology or medicine in 1970 with Julius Axelrod and Ulf von Euler.
"Dr. Katz also found that even without action potentials, lone vesicles are released now and then at the synapse gaps. These miniature events — or minis — have been found at every type of synapse that has been studied. However, since minis don't induce neurons to fire, people assumed they were inconsequential, just background noise."
s, PhD, assistant professor of pathology, cell biology and neuroscience in the Motor Neuron Center, and study leader.
Recent cell-culture studies, however, have suggested that minis do have some function and even their own regulatory mechanisms. "This led us to wonder why there would be such complicated mechanisms for regulating something that was just noise," said Dr. McCabe.
To learn more about minis, the CUMC team devised new genetic tools to selectively up- or down-regulate evoked and miniature neurotransmission in fruit flies (a commonly used model organism for neural function and development). This was the first study to identify a unique role for minis in any animal model.
When both types of neurotransmission were blocked, synapse development was abnormal. But inhibiting or stimulating evoked neurotransmission by itself had no effect on synaptic development. "When we blocked minis, synapses failed to develope," said Dr. McCabe, "and when we stimulated the release of more minis, synapses got bigger."
The study revealed that minis regulate synapse development by activating a signaling pathway in neurons using Trio and Rac1 proteins. Proteins also found in humans.
It remains to be seen exactly how minis are exerting their effects. Dr. McCabe adds: "Parallel communication occurs in computer networks. Computers communicate primarily by sending bursts of data bundled into packets. But individual computers also send out pings, or tiny electronic queries, to determine if there is a connection to other computers. Similarly, neurons may be using minis to ping connected neurons, saying in effect, 'We are connected and I am ready to communicate.'"
The researchers are currently looking into whether minis have a functional role in the mature nervous system. If so, it's possible that defects in minis could contribute to neurodegenerative disease.
•Miniature, but not evoked, neurotransmission is required for synapse development
•Miniature neurotransmission bidirectionally regulates synaptic terminal maturation
•Miniature events signal locally through the GEF Trio and the GTPase Rac1
•Miniature neurotransmission has unique and essential functions in vivo
Miniature neurotransmission is the transsynaptic process where single synaptic vesicles spontaneously released from presynaptic neurons induce miniature postsynaptic potentials. Since their discovery over 60 years ago, miniature events have been found at every chemical synapse studied. However, the in vivo necessity for these small-amplitude events has remained enigmatic. Here, we show that miniature neurotransmission is required for the normal structural maturation of Drosophila glutamatergic synapses in a developmental role that is not shared by evoked neurotransmission. Conversely, we find that increasing miniature events is sufficient to induce synaptic terminal growth. We show that miniature neurotransmission acts locally at terminals to regulate synapse maturation via a Trio guanine nucleotide exchange factor (GEF) and Rac1 GTPase molecular signaling pathway. Our results establish that miniature neurotransmission, a universal but often-overlooked feature of synapses, has unique and essential functions in vivo.
An animation of evoked neurotransmission and minis can be found at http://youtu.be/w1-KigZbF7A.
The paper is titled, "Miniature Neurotransmission Regulates Drosophila Synaptic Structural Maturation." The other contributors are Ben Jiwon Choi, Wendy L. Imlach, Wei Jiao, Mark Grbic, and Carolina Cela, (all at CUMC); Verena Wolfram and Richard A. Baines (University of Manchester, U.K.); and Ying Wu and Michael N. Nitabach (Yale School of Medicine, New Haven, CT).
The authors declare no financial or other conflicts of interests.
The study was supported by grants from the National Institutes of Health (5T32HL08774, F32NS055527, NS055035, NS056443, NS058330, GM098931, NS075572, and AG08702), the Wellcome Trust
(090798/Z/09/Z), the DANA Foundation, the Gatsby Initiative in Brain Circuitry, and the New York Presbyterian Seizure Disorders Fund.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.
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