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
Phone: (814) 865-5549

Research Interests

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

Graduate Programs


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).

A second line of research uses mouse genetics to model and investigate the molecular mechanisms underlying neuropsychiatric disorders. In particular, we are interested in the etiology of Major Depressive Disorder (MDD), a leading cause of total disability affecting about 17 percent of the human population. Recent clinical evidence points to reduced brain concentrations of GABA as a possible cause of MDD. Using targeted mutagenesis in mice, we have shown that modest deficits in GABAergic transmission are sufficient to reproduce behavioral, cognitive, cellular, endocrine, and pharmacological alterations expected of a mouse model of depression. These mice, therefore, provide strong evidence that GABA deficits are not just an epiphenomenon of MDD, but that they can, in fact, be causal for MDD. Current research relies on these mice to elucidate the detailed molecular and cellular etiology of MDD, as well as mechanisms of antidepressant drug action (reviewed in Luscher et al 2011, Mol. Psychiatry).

Selected Publications

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.

Ren, Z., Sahir, N., Murakami, S., Luellen, B.A., Earnheart, J.C., Lal, R., Kim, J.Y., Song, H., and Luscher, B. (2014). Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. Neuropharmacology, in press.

Reid, C.A., T. Kim, A.M. Phillips, J. Low, S.F. Berkovic, B. Lüscher, and S. Petrou (2013). Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology 80, 1003-1008.

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

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

Wu, X., Z. Wu, G. Ning, Y. Guo, R. Ali, R.L. Macdonald, A.L. De Blas, B Lüscher, and G Chen (2012). GABAA receptor alpha subunits play a direct role in synaptic versus extrasynaptic targeting. J. Biol. Chem. 287, 27417-30.

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

Lüscher, 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. Lüscher. 2010. GABA-A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity characteristic of melancholic depression. Biol. Psychiatry 68: 512-520.

Lee, K., R. Porteous, R. E. Campbell, B. Lüscher, and A E. Herbison.2010. Knock-down of GABA-A receptor signaling in gonadotropin-releasing hormone (GnRH) neurons has minimal effects upon fertility. Endocrinology 151: 4428-4436.

Kalscheuer, V. M., K. Hoffmann, C. Menzel, C. Fang, E. Deas, C. Fuchs, K. Venkateswarlu, N. Tommerup, L. Musante, L. Dalprà, A. Tzschach, A. Selicorni, B. Lüscher, H.-H. Ropers, K. Harvey, and R. J. Harvey. 2009. A balanced chromosomal translocation disrupting ARHGEF9 encoding the RhoGEF collybistin results in epilepsy, anxiety, aggression and defects in learning and memory. Hum. Mutat. 30: 61-68.

Yuan X., J. Yao, J. S. Qi, D. Norris, D. D. Tran, R. J. Bram, G. Chen, and B. Lüscher. 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. Lüscher. 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. Lüscher. 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. Lüscher. 2005. Distinct gamma2 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, J. P. Laurent, C. Belzung, J. M. 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., M. Lorez, J. Benson, J.-M. Fritschy and B. Lüscher (1998). Postsynaptic clustering of major GABA-A receptor subtypes requires the gamma2 subunit and gephyrin. Nat Neurosci 1, 563-571.