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1984 B.A. Williams College 1992 Ph.D. Department of Physiology & Cellular Biophysics
Columbia University – Presbyterian Medical Center,
1993 M.D. Columbia University – Presbyterian Medical Center Postdoctoral Training:
PGY 1 medical intern Department of Internal Medicine New York Hospital/Cornell University Medical Center
PGY 2-4 neurological resident Department of Neurology University of California, Los Angeles Medical Center
Postdoctoral research fellow Laboratory of Dr. H.R. Horvitz Department of Biology Massachusetts Institute of Technology
Laboratory of Dr. F.M. Benes Department of Psychiatry McLean Hospital/Harvard Medical School
Research Associate Laboratory of Dr. C.P. Hunter Department of Molecular and Cellular Biology Harvard University
Licensure and Certification:
Hospital or Affiliated Institution Appointments:
Director of the Pharmacogenomics Section
1990-present Society for Neuroscience
1995-present American Academy of Neurology
Awards and Honors:
Augustus S. Rose Award for Excellence in Teaching (UCLA)
HHMI Postdoctoral Research Fellowship for Physicians
NINDS K08 Mentored Clinical Scientist Development Award
Research, Teaching, and Clinical Contributions
Progress in drug development for the treatment of psychosis has been slowed by a
poor understanding of the mechanisms of action of antipsychotic drugs. Therefore, I use pharmacogenomic studies in the nematode Caenorhabditis elegans
to identify novel signal transduction pathways through which antipsychotic drugs exert their biological effects. Large-scale genetic screens can be performed in which millions of individuals are mutated and screened for phenotypes of interest, an approach not possible in knockout or transgenic mice. Such screens allow an unbiased approach to discovery of genetic targets without prior knowledge of their biological roles.
I have characterized the effects of a variety of antipsychotic drugs on the behavior
and development of C. elegans
but have focused primarily on clozapine. Clozapine is the most effective medication for the management of treatment-refractory schizophrenia. The molecular mechanisms underlying clozapine’s therapeutic and side effects remain unknown, and a clearer understanding of these mechanisms would facilitate the design of improved drugs. When applied to adults, clozapine modulates several C. elegans
behaviors, including egg-laying, pharyngeal pumping, and locomotion. When applied to embryos, clozapine, and only clozapine, among all the antipsychotic drugs, arrests larval development. Novel genetic targets underlie these clozapine-induced phenotypes,
because many of them are unaffected by mutations in genes required for the action of dopamine and serotonin.
I discovered that genes within the insulin-signaling pathway mediate clozapine-
induced larval arrest. These genes are conserved in humans and include the insulin receptor daf-2
and the phosphatidylinositol-3-kinase age-1
. I also conducted a genome-wide RNA interference (RNAi)-based screen for suppressors of clozapine-induced larval arrest. This RNAi screen is, to my knowledge, the first chemical genetic screen for antipsychotic drug targets in an animal. The screen covered ~17,000 C. elegans
genes and led to the identification of ~40 suppressors of clozapine-induced larval arrest. The screen confirmed the involvement of the insulin signaling pathway. Several of the newly identified suppressors have human orthologs linked to schizophrenia but have not been previously identified as antipsychotic drug targets. These suppressors may define new pathways by which clozapine produces its unique effects. These genes also pose inviting new drug targets for the development of compounds that replicate clozapine’s therapeutic effects but that do not share its toxicities.
Other projects ongoing in my group include studies of clozapine-induced behaviors in
knockout mice and reverse genetic studies of neurological disease gene orthologs in C. elegans
. As an example of the latter approach, I analyzed lis-1
, the C. elegans
ortholog of the human disease gene Lis1
, which causes lissencephaly. I found that loss of lis-1
activates the spindle checkpoint resulting in mitotic arrest, followed by ced-3
-dependent programmed cell death. These results place the spindle checkpoint upstream of the programmed cell death pathway and suggest that apoptosis may contribute to the cell-sparse pathology of lissencephaly.
I participate in Neurology rounds at McLean Hospital and teach medical students and
residents under the supervision of Dr. Bruce Price. I currently mentor two postdoctoral researchers and two technical research assistants in the Mailman Research Center at McLean Hospital.
1. Buttner, N., Siegelbaum, S.A., and Volterra, A. Direct modulation of Aplysia
channels by a 12-lipoxygenase metabolite of arachidonic acid. Nature 1989;342:553-5.
2. Volterra, A., Buttner, N. and Siegelbaum, S.A. Direct opening of S-type K+ channels of
sensory neurons by 12-lipoxygenase metabolites. Adv. Prostaglandin Thromboxane. Leukotriene Res. 1991;21B:727-30.
3. Buttner, N., Geschwind, D.H., Jen, J., Perlman, S., Pulst, S.M., Baloh, R.W. Oculomotor
phenotypes in the SCA syndromes. Archives of Neurology 1998;55:1353-7.
4. Leibeskind, D.S., Ostrzega, N., Wasterlain, C.G., Buttner, E.A. Neurologic
manifestations of disseminated infection with Mycobacterium abscessus.
5. Buttner, N., Siegelbaum, S.A. Antagonistic modulation of a hyperpolarization-activated
chloride current in Aplysia
sensory neurons by SCP and FMRFamide. Journal of Neurophysiology
6. Buttner, E.A., Gil-Krzweska, A., Rajpurohit, A., Hunter, C. Progression from Mitotic
Catastrophe to Cell Death Requires the Spindle Checkpoint in C. elegans
. Developmental Biology 2007;305:397-410.
7. Buttner, E.A., Bhattacharyya, S., Walsh, J., Benes, F.M. DNA fragmentation is increased
in non-GABAergic neurons in bipolar disorder. Schizophrenia Research 2007; 93:33-41.
8. Karmacyarya, R., Sliwoski, G.R., Lundy, M.Y., Suckow, R.F., Cohen, B.M., Buttner,
E.A. Clozapine Interaction with Phosphatidyl Inositol 3-Kinase (PI3K)/Insulin-Signaling Pathway in Caenorhabditis elegans
. Neuropsychopharmacology 2009;34:1968-78.
9. Karmacharya, R., Demarco, S., Ortiz, A., Lundy, M.Y., Cohen, B.M., Buttner, E.A.
Trace Amine Pathways Mediate Behavioral Effects of Antipsychotics in Caenorhabditis elegans.
Journal of Neuroscience Research, 2009; submitted.
10. Gil-Krzewska, A.J. Farber, E., Buttner, E.A., Hunter, C.P. Regulators of the Actin
Cytoskeleton Mediate Lethality in a Caenorhabditis elegans dhc-1
mutant. Molecular Biology of the Cell, 2009; submitted.
Reviews, Chapters and Editorials
1. Siegelbaum, S.A., Volterra, A., Buttner, N. Antagonistic modulation of the S-K+ channel
sensory neurons by lipoxygenase metabolites of arachidonic acid and cAMP. In: J. Vanderhoek, editor. Biology of cellular transducing signals.
New York: Plenum; 1989. p 371-9.
2. Buttner, E.A., Price, B.H. Depression: Neurology, Psychiatry and Neuroscience. In
3. Sliwoski, G.R., Buttner, E.A. The Nematode Caenorhabditis elegans
is a Model System
for the Study of Psychiatric Disease Genes. In preparation.
WorldLink Medical Setting the Record Straight on Hormones and Cancer No Study Shows that Testosterone Causes Cancer With all due respect, the doctor that suggests that HRT causes cancer is perhaps unaware of the medical literature. Testosterone does not cause cancer. It may cause it to grow once prostate cancer is established, but no study shows that testosterone causes the cancer. On
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