May 20, 2002 Electrical excitability is harnessed by the body for a myriad of physiological functions including communication between nerve cells and regulation of heartbeat. Diseases caused by pathological electrical over-excitability, such as epilepsy and cardiac arrhythmia, can be catastrophic. A team of biologists at New York University has discovered a new and efficient method of “silencing” neurons – effectively blocking their electrical excitability – by introducing a new twist on a standard genetic technique.
The new method sheds light on the central role electrical activity in neurons plays in governing the body’s circadian rhythms, or internal clock. It may also help in the future development of more effective treatments for diseases that are caused by aberrant electrical activity in neurons and other electrically excitable cells and tissues. The findings were published in the May 17 issue of Cell.
Led by Todd C. Holmes, Assistant Professor of Biology at NYU, the team developed an experimental test case to control the electrical activity of a specific neural circuit in Drosophila by directing the expression of modified potassium channel genes. Potassium channels act as the “brakes” for electrical excitability. The NYU team used a channel modified to be a super-potassium channel for their work. Ordinarily, neuronal activity varies over a broad range, and moment-to-moment changes in electrical activity serve to encode information. They reasoned that expression of modified potassium channels could be used to attenuate such moment-to-moment changes in electrical activity.
The team’s test circuit for controlling electrical excitability was the circadian pacemaker neuron circuit. In pacemaker neurons, the electrical activity regulates the molecular clock of an organism, which keeps it on a 24-hour (circadian) cycle of rest and activity.
By introducing modified potassium channel genes into the circadian pacemaker neurons, the team was able to hold the neurons into a negative potential, which silences the neurons and halts their flow of electrochemical information. Surprisingly, this resulted also in a complete deactivation of the organism’s free-running molecular clock that ordinarily cycles with a 24-hour rhythm. Free-running refers to challenging the clock with constant darkness. Virtually all organisms are capable of retaining their normal cycle of circadian activity when living in constant darkness over many days. The new result of the NYU team’s research indicates a previously unsuspected centrality of electrical activity in the operation of the molecular clock.
“Previous work has focused on the regulation of the circadian rise and fall of the levels of dedicated clock proteins that are components of the molecular clock. But our research indicates that electrical activity is an essential element in the clock itself. This may also be the case for other organisms as well, perhaps even humans,” Holmes said.
Research in the area of circadian rhythms has exploded over the last decade. Much of the prior research took a forward genetics approach, through which many thousands of mutant animals are created by exposure to treatments that randomly induce mutations, then researchers screen for behavioral changes in organisms and seek to identify the responsible genes. Holmes’ team’s research takes a reverse genetics approach, through which researchers alter or introduce a known gene and watch what effect it has on an organism, thereby getting an idea of the gene's function. The result was not only a very specific discovery regarding electrical activity and the molecular circadian clock, but a better understanding of how to control electrical excitability in general.
“This discovery has already provided important insights into the control of fruit fly behavior. Just as importantly, it also provides us with a wonderful new set of tools to explore mammalian nervous systems,” said Henry A. Lester, Bren Professor of Biology at the California Institute of Technology.
“I predict that this general approach will have an astonishing range of applications in neurobiology. We may look forward someday to applying these genetic techniques towards diseases of electrical excitability,” Holmes noted.
Todd Holmes received his BA in biology at the University of California before earning his PhD in neurobiology at MIT. He joined NYU’s faculty in 1998. His research focuses on ion channel regulation and bioengineering. The article in Cell, entitled "Electrical Silencing of Drosophila Pacemaker Neurons Stops the Free-Running Circadian Clock" was co-authored by Michael N. Nitabach, a Postdoctoral Fellow working in the Holmes laboratory and Justin Blau, Assistant Professor of Biology, both of NYU.
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