| | Principal Investigators
| Howard A. Nash, M.D., Ph.D. |
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Dr. Nash received his M.D and Ph.D. degrees from the University of Chicago, where he worked on ionic interactions of membrane phospholipids. Following a pediatric internship he joined NIMH, first as a Research Fellow and subsequently as an Investigator in the Laboratory of Neurochemistry. In 1984 Dr. Nash joined the Laboratory of Molecular Biology and continued his studies of the protein-DNA interactions that govern site-specific genetic recombination.
He was elected to the American Academy of Arts and Sciences in 1989 and to the National Academy of Sciences in 1990. In recent years Dr. Nash’s principal interest has been the use of genetics in the fruit fly, Drosophila melanogaster, to investigate mechanisms and consequences of general anesthesia.
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| Research Interests |
General anesthetics (GAs) produce their effects by depressing arousal, the state of neural excitability that governs an organism's ability to interact with its environment. In addition to their value in the clinic, these poorly understood drugs thus provide a window into the neurobiology of arousal. Mutations that influence the effectiveness of anesthetics should identify genes that are important for this state and the ways it can be undermined.
To enable an unbiased approach to finding such genes, we study anesthesia in the fruit fly. We previously showed that Drosophila and vertebrates have similar sensitivities to volatile GAs, suggesting that their molecular targets are conserved. And we found that the fly's elementary neural functions are largely preserved under anesthesia, just as in vertebrates. Thus, genes identified in Drosophila are not only of intrinsic interest but should be informative about excitability in higher organisms.
Recent highlights from our work include: 1) The fly genome contains a few segments that, when their copy number is halved, confer altered sensitivity to GAs. The result points to genes whose function is limiting for proper levels of arousal and, since copy number variation is common in humans, has strong clinical implications. 2) Although the arousal system has been assumed to be monotonically stimulated by illumination, measurement of anesthesia in flies under light vs. dark conditions demonstrates that light has both positive and negative influences on arousal, a balance that can be disproportionated by mutation. 3) Patch clamp studies of fly larval motorneurons show that a volatile GA depresses excitability by activating a hyperpolarizing leak channel.
This provides the best evidence to date that anesthesia mechanisms are conserved at the electrophysiological level between vertebrates and invertebrates. 4) An important contributor to the excitability of neurons in all metazoans is an unusual ion channel that serves as a depolarizing leak. We found that a previously unannotated fly gene, one encoding a highly conserved protein, is specifically required for channel function
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| Representative Selected Recent Publications: |
- Alone, D.P., Rodriguez, J.C, Noland, C.L., and Nash, H.A.: Impact of Gene Copy Number Variation on Anesthesia in Drosophila melanogaster. Anesthesiology, In press, 2009.
- Cheng, Y. and Nash, H. A.: Visual mutations reveal opposing effects of illumination on arousal in Drosophila. Genetics, 178, 2413-2415, 2008.
- Sandstrom, D. J.: Isoflurane Reduces Excitability of Drosophila Larval Motoneurons by Activating a Hyperpolarizing Leak Conductance. Anesthesiology , 108, 434-446, 2008.
- Humphrey, J., Hamming, K.,Thacker, C., Scott, R., Sedensky, M., Snutch, T., Morgan, P., and Nash, H.:
A Putative Cation Channel and Its Novel Regulator: Cross-Species Conservation of Effects on General Anesthesia,
Curr. Biol., 17, 624-629, 2007.
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Address:
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Dr. Howard A. Nash
Laboratory of Molecular Biology, NIMH
Porter Neuroscience Research Center
Building 35, 1B-1002
35 Convent Dr, MSC 3736
Bethesda, MD 20892-3736 |
| Phone: |
301-402-1041 |
| Email Dr. Nash |
| Fax: |
301-402-0245 |
| Lab Web Site: |
No website available |
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