MAILMAN RESEARCH CENTER

Laboratory of Genetic Neuropharmacology

Picture taken from Trends Pharmacol Sci 2001;22:188-94
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The Laboratory of Genetic Neuropharmacology (LGN) is interested in studying the functions of GABA_A receptor subtypes in the central nervous system. GABA_A receptors are the molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions. In order to identify the functional role of individual GABA_A receptors subtypes, we have introduced point mutations into individual GABA_A receptor subunit genes which abolish the action of benzodiazepines or general anesthetics, e.g. diazepam and propofol, respectively. However , the mutant receptors still respond to the physiological neurotransmitter GABA. Moreover, we have generated “floxed” alleles which allow to knock out the respective subunit in a tissue-specific manner either via a cross with cre transgenic mice or via injection of cre-expressing viruses into defined brain regions. These animal models will be analyzed using biochemical, morphological and behavioral methods. The LGN also collaborates with researchers at other institutions, e.g. Stanford University, UCSF, University of Wisconsin, Imperial College of Science and Technology (London), University of Tübingen, ETH Zurich and the University of Zurich. The identification of functions of individual GABA_A receptor subtypes is envisioned to enhance our understanding of processes underlying nervous system function and to lead to novel therapeutic strategies for the treatment of anxiety, psychotic, memory and mood disorders.

Laboratory of Genetic Neuropharmacology
(click to enlarge)

In collaboration with the Psychiatric Disease Initiative at the Broad Institute of MIT and Harvard in Cambridge, MA, the LGN will launch a research program aimed at the functional characterization of novel candidate genes for schizophrenia and bipolar disorder in genetically modified animals.

Personnel

Uwe Rudolph, M.D. - Director of the Laboratory of Genetic Neuropharmacology and appointment pending as Associate Professor of Psychiatry, Harvard Medical School
Kiersten S. Smith, Ph.D. - Postdoctoral Fellow
Carolin Straub, Research Fellow, and graduate student (University of Zurich)
Hewmun Lau, B.Sc., Associate in Psychiatry

Selected Publications

Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy J-M, Martin JR, Bluethmann H, Möhler H.Benzodiazepine actions mediated by specific γ-aminobutyric acid(A) receptor subtypes. Nature 1999;401:796-800.
Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy J-M, Rülicke T, Bluethmann H, Möhler H, Rudolph U.Molecular and neuronal substrate for the selective attenuation of anxiety. Science 2000;290:131-34.
Crestani R, Keist R, Fritschy J-M, Benke D, Vogt K, Prut L, Blüthmann H, Möhler H, Rudolph U.Trace fear conditioning involves hippocampal α5 GABA_A receptors. Proc Natl Acad Sci USA 2002;99:8980-5.
Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U.General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA_A receptor β3 subunit. FASEB J (December 3, 2002) doi: 10.1096/fj.02-0611fje (Full paper) FASEB J 2003;17:250-2. (Summary)
Fagiolini M, Fritschy J-M, Löw K, Möhler H, Rudolph U, Hensch, TK.Specific GABA_A circuits for visual cortical plasticity. Science 2004;303:1681-3.
Zeller A, Arras M, Lazaris A, Jurd R, Rudolph U.Distinct molecular targets for the central respiratory and cardiac actions of the general anesthetics etomidate and propofol. FASEB J (July 26, 2005) doi:10.1096/fj.04-3443fje (Full paper) FASEB J 2005;19:1677-9. (Summary)
Yee BK, Keist R, von Boehmer L, Studer R, Benke D, Hagenbuch N, Dong Y, Malenka RC, Fritschy J-M, Bluethmann H, Feldon J, Möhler H, Rudolph U.A schizophrenia-related sensorimotor deficit links α3-containing GABA_A receptors to a dopamine hyperfunction. Proc Natl Acad Sci USA 2005;102:17154-9.

Selected Reviews

Rudolph U, Möhler H. Analysis of GABA_A receptor function and dissection of pharmacology of benzodiazepines and general anesthetics through mouse genetics. Ann Rev Pharmacol Toxicol 2004;44:475-98.
Rudolph U, Antkowiak B.Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 2004;5:709-20.
Rudolph U, Möhler H. GABA-based therapeutic approaches: GABA_A receptor subtype functions. Curr Opin Pharmacol 2006;6:18-23.