Penn State Biology and Molecular Biology Home Page. Includes image map to PSU Home, BMB Home, and Eberly College of Science Home.

Bernhard Lüscher

Professor of Biology, BMB and Psychiatry

221 Life Sciences Building, University Park, PA 16802
Phone: (814) 865-5549
Email: BXL25@psu.edu

Diploma in Biochemistry, ETH Zurich
Ph.D. in Molecular Biology, University of Zurich

Lüscher Lab Web Site

 

Molecular Neurobiology of Inhibitory Synapses

Our research is focused on the structure, function, and mechanisms of postsynaptic targeting of the mammalian type A receptors for gamma-aminobutyric acid (GABA) and on the mechanisms by which these receptors regulate learning, memory, mood and other brain functions.

GABA-A receptors are the principal ion channels that mediate inhibitory neurotransmission in the brain. They are typically clustered at postsynaptic sites of GABAergic inhibitory synapses, which represent up to 40% of all synapses in the brain. Structurally, GABA-A receptors are heteropentameric chloride channels that include a number of binding sites for clinically important drugs, most notably the benzodiazepines (BZs), diverse general anesthetics, as well as endogenously produced neurosteroids and alcohol. By modulating GABA-A receptor function these ligands can enhance or inhibit a wide variety of CNS states, including vigilance, anxiety, pain, epileptic activity, and memory. Thus, GABA-A receptors serve as important targets for therapeutic modulation of vitally important brain functions and their proper regulation is essential for maintaining mental health. Increasing evidence suggest that GABA-A receptor are critically important for normal postnatal development of the brain.

Differential spatio-temporal expression and assembly of a multitude of subunits encoded by at least 19 distinct genes (a1-6, b1-3, g1-3, , ,) leads to pronounced GABA-A receptor heterogeneity. Most types of GABA-A receptor consist of alpha and beta subunits together with the gamma2 subunit. We are specifically interested in molecular and cellular mechanism that regulate the intracellular trafficking and concentration of these receptors at synapses and thereby contribute to dynamic regulation of inhibitory synapses and higher order brain function. In addition, recent studies from our lab indicate that subtle changes in GABA-A receptor expression during development have profound effects on adult hippocampal neurogenesis, and thereby appear to contribute to the vulnerability for anxiety and mood disorders. Hence, a second objective of our laboratory is to elucidate the molecular and cellular mechanism by which subtle changes in GABA-A receptor expression during development lead to lasting downstream changes in brain function and behavior in adulthood.

In all these endeavors we use a multidisciplinary approach that includes mouse genetics, molecular and cell biology, biochemistry, electrophysiology, neuroanatomy, neuropharmacology as well as mouse behavioral approaches.            


[Schematic view of a GABAergic inhibitory synapse, consisting of a GABAergic termina and the underlying postsynaptic membrane].

Representative Publications

  • Yuan X., J. Yao, J.S. Qi, D. Norris, D.D. Tran, R.J. Bram, G. Chen and B. Luscher (2008) Calcium-Modulating cyclophilin Ligand regulates membrane trafficking of postsynaptic GABA A receptors. Mol. Cell. Neurosci. in press.
  • Deng L., J. Yao, C. Fang, N. Dong, B. Luscher and G. Chen (2007). Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures. J. Neurosci. 27,10860-1086.
  • Earnheart J.C., C. Schweizer, F. Crestani, T. Iwasato, S. Itohara, H. Mohler, and B. Luscher (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J. Neurosci. 27, 3845-3854.
  • Qi J.S., J. Yao, C. Fang, B. Luscher, G. Chen (2006) Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. J. Physiol. 577:579-590.

  • Fang C, L. Deng , C.A. Keller , M. Fukata , Y. Fukata , G. Chen, and B. Luscher (2006) GODZ-mediated palmitoylation of GABA-A receptors is required for normal assembly and function of GABAergic inhibitory synapses. J Neurosci. 26, 12758-68.

  • Alldred, M.J., J. Mulder-Rosi, S.E. Lingenfelter, G. Chen, and B. Luscher (2005). Distinct gamma2 subunit domains mediate clustering and synaptic function of postsynaptic GABA-A receptors and gephyrin. J. Neurosci. 25, 594-603

  • Harvey, K., I.C. Duguid, M.J. Alldred, S.E. Beatty, H.Ward, N.H. Keep, S.E. Lingenfelter, B.R. Pearce, J. Lundgren, M.J . Owen, T.G. Smart, B. Luscher , M.I. Rees, and R.J. Harvey (2004). The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci. 25, 5816 -5826. (Editorial comment in same issue)
  • Luscher B, CA Keller (2004) Regulation of GABA-A receptor trafficking and channel activity in functional plasticity of inhibitory synapses. Pharmacol Therapeut. 102, 195-221.
  • Keller CA, X. Yuan, M. Alldred, P. Panzanelli, M.L. Martin, M. Sassoè-Pognetto and B. Luscher (2004). The gamma2 subunit of GABA-A receptors is a substrate for palmitoylation by GODZ J. Neurosci. 24, 5881-5891. (Cover illustration of issue)
  • Fritschy, J.M., C. Schweizer, I. Brünig and B. Luscher (2003) Pre- and postsynaptic mechanisms regulating the clustering of GABA-A receptors. Biochem. Soc. Trans. 31, 889-891.
  • Schweizer C., S. Balsiger, H. Bluethmann, I.M. Mansuy, J-M. Fritschy, H. Mohler, and B. Luscher (2003). The gamma2 subunit of GABA A receptors is required for maintenance of receptors at mature synapses. Mol. Cell. Neurosci. 24, 442-450.
  • Luscher, B. (2002) GABA-A and GABA-C receptors: regulation of assembly, localization, clustering and turnover. Assembly and Targeting of Ion Channels . Eds. J. Henley and S. Moss, Oxford University Press, Oxford (UK), p. 192-218.
  • Brünig, I., A. Suter, I. Knüsel, B. Luscher and J.M. Fritschy (2002) GABAergic terminals are required for postsynaptic clustering of dystrophin, but not of GABA-A receptors and gephyrin. J. Neurosci. 22, 4805-4813.
  • Luscher , B and C.A. Keller (2001). Ubiquitination, Proteasomes and GABA-A Receptors. Nature Cell Biol 3, Oct. 2001. E232-E233.
  • Baer, K., Essrich, C., Balsiger, S., Wick, M., Harris, R.A., Fritschy, J.-M. & Lüscher, B. (2000) Rescue of gamma2 subunit-deficient mice by transgenic overexpression of the GABAA receptor gamma2S or gamma2L subunit isoforms. Eur. J. Neurosci., 12, 2639-43.
  • Baer, K., Essrich, C., Benson, J. A., Benke, D., Bluethmann, H., Fritschy, J.-M. & Lüscher, B. (1999). Postsynaptic clustering of GABA-A receptors by the gamma3 subunit in vivo. Proc. Natl. Acad. Sci. U S A, 96, 12860-12865.
  • Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J. M., Lüscher, B. & Mohler, H. (1999). Decreased GABA-A-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2, 833-839.
  • Essrich, C., Lorez, M., Benson, J., Fritschy, J.-M., and Lüscher, B. (1998). Postsynaptic clustering of major GABA-A receptor subtypes requires the gamma 2 subunit and gephyrin. Nature Neurosci. 1, 563-571.
  • Günther, U., Benson, J., Benke, D., Fritschy, J.-M., Reyes, G., Knoflach, F., Crestani, F., Aguzzi, A., Arigoni, M., Lang, Y., Bluethmann, H., Mohler, H., and Lüscher, B. (1995). Benzodiazepine-insensitive mice generated by targeted disruption of the 2 subunit gene of GABA-A receptors. Proc. Natl. Acad. Sci. U S A 92, 7749-7753.

Search the MEDLINE database at PubMed for articles by B. Luscher

©2005 Penn State University Department of Biochemistry & Molecular Biology, 108 Althouse Lab, University Park, PA 16802. Privacy and legal statements.
Back to Penn State Home Page. Back to Biochemistry & Molecular Biology home page. Visit Eberly College of Science.