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Bernhard Luscher

Bernhard Luscher

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Professor of Biology, Biochemistry and Molecular Biology, and Psychiatry

209 Life Sciences
University Park, PA 16802
Phone: (814)865-5549
Lab Address: 203/208 Life Sciences
Lab Phone: (814) 865-5563
Email:

Education

  1. Ph.D. in Molecular Biology, University of Zurich, 1987
  2. Diploma in Biochemistry, ETH Zurich, 1983

Postdoc Training

  1. UC Berkeley

Research Interests

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).

A first 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 likely 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).

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, physiologically important 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

Kilpatrick C. L., Murakami, S., Feng, M., Wu, X., Lal, R., Chen, G., Du, K. and 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.

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.

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

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

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

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.

Lee, K., R. Porteous, R. E. Campbell, B. Luscher, 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. Luscher, 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. Luscher. 2008. Calcium-Modulating cyclophilin Ligand regulates membrane trafficking of postsynaptic GABA-A receptors. Mol. Cell. Neurosci. 38: 277-289.

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: 10860-10869.

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.

Qi J., J. Yao, C. Fang, B. Luscher, and 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: 12758-12768.

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.