Biochemistry and Molecular Biology
Penn State Science
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Bernhard Lüscher

Bernhard Lüscher

Main Content

  • Professor of Biology and
  • Professor of Biochemistry and Molecular Biology
209 Life Sciences Building
University Park, PA 16802
Email: bxl25@psu.edu
Phone: (814) 865-5549

Research Interests

Understanding of the role and function of GABAergic transmission in health and disease
 
 

Graduate Programs

BIOL, BMMB, MCIBS, NEURS

Research Summary

We are working to improve our understanding of the role and function of GABAergic transmission in health and disease. GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain and known to exert most of its function by activation of so-called GABA-A receptors. These receptors are GABA-gated chloride channels and they serve as the targets of several classes of clinically and therapeutically important psychoactive drugs, most notably the benzodiazepines (Valium, Xanax, Versed, etc). Based on knowledge derived from these drugs, GABA-A receptors are known to modulate virtually every higher order brain function (learning, memory, cognition, emotion, pain, motivation, muscle tension, etc).

As a first line of research we study mechanisms that regulate GABAergic synapses and thereby contribute to regulation of the above brain functions. In particular, we study mechanisms that control the formation and functional regulation of GABAergic inhibitory synapses including the trafficking of GABA(A) receptors, receptor-associated proteins, and post-translational receptor modifications. We have identified a palmitoyltransferase that palmitoylates GABA-A receptors and, thereby, contributes to structural and functional modulation of GABAergic synapses (Fang et al 2006). Ongoing studies use mouse genetics to further understand the role of GODZ in the regulation of GABAergic transmission and normal brain function (reviewed in Luscher et al, 2011, Neuron).

As a second line of research we are interested in mechanisms that control the formation and functional regulation of GABAergic inhibitory synapses including the trafficking of GABA(A) receptors, receptor-associated proteins, and post-translational receptor modifications. We have identified a palmitoyltransferase(GODZ/DHHC3) that palmitoylates GABA-A receptors and thereby  contributes to structural and functional modulation of GABAergic synapses (Fang et al 2006). Ongoing studies use mouse genetics to further understand the role of GODZ/DHHC3 in the regulation of GABAergic transmission and normal brain function (reviewed in Luscher et al, 2011, Neuron), and in regulated trafficking of other plasma membrane proteins.

 

Selected Publications

Du K., S. Murakami, Y. Sun, C. Kilpatrick and B. Luscher (2017). DHHC7 palmitoylates Glut4 and regulates Glut4 membrane translocation.  J. Biol. Chem. 292, 2979-2991  Recommended by F1000.

Kilpatrick C. L., Murakami, S., Feng, M., Wu, X., Lal, R., Chen, G., Du, K., Luscher, B. (2016) Dissociation of Golgi-associated DHHC-type zinc finger protein (GODZ) and sertoli cell gene with a zinc finger domain-β (SERZ-β)-mediated palmitoylation by loss of function analyses in knockout mice.  J. Biol. Chem. 291, 27371-27386

Fuchs T,  Jefferson SJ, Hooper H, Yee P-HP, Maguire J, and Luscher B. (2016). Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state. Molecular Psychiatry, Epub online.  Commentary by Zhang et al Mol Psych.  Recommended by F1000.

Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T, Stellwagen D, and Luscher B (2016): Bidirectional homeostatic regulation of a depression-related brain state by GABAergic deficits and ketamine treatment. Biol Psychiatry, 80, 457–468.    Commentary by JW Murrough.

Ren, Z., Sahir, N., Murakami, S., Luellen, B.A., Earnheart, J.C., Lal, R., Kim, J.Y., Song, H., and Luscher B. (2015). Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. Neuropharmacology 88, 171-179.

Luscher B, Fuchs T (2015). GABAergic control of depression-related brain states, In Diversity and function of GABA receptors: A tribute to Hanns Möhler, Part B. Advances in Pharmacology 73, 97-144.  Recommended by F1000.

Dejanovic, B., Semtner, M., Ebert, S., Lamkemeyer, T., Neuser, F., Luscher, B., Meier, J.C., and Schwarz, G. (2014). Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses. PLoS Biol.12, e1001908.

Shen, Q., T. Fuchs, N. Sahir, and B. Luscher. 2012. GABAergic control of critical developmental periods for anxiety- and depression-related behavior in mice. PLoS One, 7 (10), e47441

Song, J, C. Zhong, M. Bonaguidi, D. Hsu, H. Davoudi, Y. Gu, K. Meletis, S. Ge, G. Enikolopov, K. Deisseroth. B. Luscher, K. Christian, G.-l. Ming and H. Song. 2012. Neuronal circuitry mechanism regulating adult quiescent neural stem cell fate decision. Nature 489, 150-154.

Luscher B., T. Fuchs and C. Kilpatrick. 2011. GABA-A receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 12, 385-409.

Luscher, B., Q. Shen, and N. Sahir. 2011. The GABAergic deficit hypothesis of major depressive disorder. Mol. Psychiatry 15: 383-406.

Shen Q., R. Lal, B. A. Luellen, J. C. Earnheart, A. M. Andrews,  and B. Luscher. 2010. GABA-A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity characteristic of melancholic depression. Biol. Psychiatry 68: 512-520.

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. 38: 277-289.

Earnheart, J. C., C. Schweizer, F. Crestani, T. Iwasato, S. Itohara, H. Mohler, B. Luscher. 2007. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of chronic trait anxiety and depression states. J. Neurosci. 27: 3845.

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: 12758-12768.

Alldred, M. J., J. Mulder-Rosi, S. E. Lingenfelter, G. Chen, and B. Luscher. 2005. Distinct ?2 subunit domains mediate clustering and synaptic function of postsynaptic GABA-A receptors and gephyrin. J. Neurosci. 25: 594-603.

Crestani F, M. Lorez, K. Baer, C. Essrich, D. Benke, JPLauren, C. Belzung, JM Fritschy, B. Luscher and H. Mohler. 1999. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat. Neurosci. 2, 833-839.

Essrich C, Lorez M, Benson JA, Fritschy JM, B. Luscher. 1998. Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci. 1:563-71.