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Bernhard Luscher

TitleProfessor of Biology, Biochemistry and Molecular Biology, and Psychiatry
InstitutionEberly College of Science
DepartmentBiology
Address221 Life Sciences Bldg
University Park, PA 16802
Phone8148655549
Other Positions
TitleProfessor of Biology, Biochemistry and Molecular Biology, and Psychiatry
InstitutionEberly College of Science
DepartmentBiochemistry and Molecular Biology

TitleDirector CMIND
InstitutionHuck Institutes of the Life Sciences
DepartmentCMIND

TitleProfessor of Biology, Biochemistry and Molecular Biology, and Psychiatry
InstitutionEberly College of Science
DepartmentPsychiatry


 Overview 
 overview
EDUCATION:

Diploma in Natural Sciences/Biochemistry, ETH Zurich, 1983
Ph.D. in Molecular Biology, University of Zurich, 1987
Postdoctoral training, UC Berkeley and University of Zurich

GRADUATE PROGRAM AFFILIATIONS:
Neuroscience, MCIBS, Biology, BMMB

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). As such they are known to modulate virtually every higher order brain function (learning memory, cognition, emotion, pain, etc).

A first area of interest are mechanisms that control the formation of GABAergic inhibitory synapses including the trafficking of GABA(A) receptors, receptor-associated proteins, and post-translational receptor modifications. In particular, we have identified a so-called palmitoyltransferase (GODZ), i. e an enzyme that palmitoylates GABA(A) receptors. GODZ thereby contributes to structural and functional modulation of GABAergic synapses (Fang et al 2006). Ongoing studies use mouse genetics, biochemical and cell biological approaches 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 investigates the molecular and cellular 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).



 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Luscher B, Fuchs T. GABAergic control of depression-related brain States. Adv Pharmacol. 2015; 73:97-144.
    View in: PubMed
  2. McBain CJ, Kittler J, Luscher B, Mody I, Orser BA. GABAergic signaling in health and disease. Neuropharmacology. 2015 Jan; 88:1.
    View in: PubMed
  3. Ren Z, Sahir N, Murakami S, Luellen BA, Earnheart JC, Lal R, Kim JY, Song H, Luscher B. Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. Neuropharmacology. 2015 Jan; 88:171-9.
    View in: PubMed
  4. Dejanovic B, Semtner M, Ebert S, Lamkemeyer T, Neuser F, Lüscher B, Meier JC, Schwarz G. Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses. PLoS Biol. 2014 Jul; 12(7):e1001908.
    View in: PubMed
  5. Luscher B, Fuchs T. Adult hippocampal neurogenesis in the absence of serotonin (Commentary on Diaz et al.). Eur J Neurosci. 2013 Sep; 38(5):2649.
    View in: PubMed
  6. Reid CA, Kim T, Phillips AM, Low J, Berkovic SF, Luscher B, Petrou S. Multiple molecular mechanisms for a single GABAA mutation in epilepsy. Neurology. 2013 Mar 12; 80(11):1003-8.
    View in: PubMed
  7. Shen Q, Fuchs T, Sahir N, Luscher B. GABAergic control of critical developmental periods for anxiety- and depression-related behavior in mice. PLoS One. 2012; 7(10):e47441.
    View in: PubMed
  8. Song J, Zhong C, Bonaguidi MA, Sun GJ, Hsu D, Gu Y, Meletis K, Huang ZJ, Ge S, Enikolopov G, Deisseroth K, Luscher B, Christian KM, Ming GL, Song H. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature. 2012 Sep 6; 489(7414):150-4.
    View in: PubMed
  9. Wu X, Wu Z, Ning G, Guo Y, Ali R, Macdonald RL, De Blas AL, Luscher B, Chen G. ?-Aminobutyric acid type A (GABAA) receptor a subunits play a direct role in synaptic versus extrasynaptic targeting. J Biol Chem. 2012 Aug 10; 287(33):27417-30.
    View in: PubMed
  10. Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011 May 12; 70(3):385-409.
    View in: PubMed
  11. Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011 Apr; 16(4):383-406.
    View in: PubMed
  12. Shen Q, Lal R, Luellen BA, Earnheart JC, Andrews AM, Luscher B. gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry. 2010 Sep 15; 68(6):512-20.
    View in: PubMed
  13. Lee K, Porteous R, Campbell RE, Lüscher B, Herbison AE. Knockdown of GABA(A) receptor signaling in GnRH neurons has minimal effects upon fertility. Endocrinology. 2010 Sep; 151(9):4428-36.
    View in: PubMed
  14. Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R, Tommerup N, Dalprà L, Tzschach A, Selicorni A, Lüscher B, Ropers HH, Harvey K, Harvey RJ. A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat. 2009 Jan; 30(1):61-8.
    View in: PubMed
  15. Yuan X, Yao J, Norris D, Tran DD, Bram RJ, Chen G, Luscher B. Calcium-modulating cyclophilin ligand regulates membrane trafficking of postsynaptic GABA(A) receptors. Mol Cell Neurosci. 2008 Jun; 38(2):277-89.
    View in: PubMed
  16. Deng L, Yao J, Fang C, Dong N, Luscher B, Chen G. Sequential postsynaptic maturation governs the temporal order of GABAergic and glutamatergic synaptogenesis in rat embryonic cultures. J Neurosci. 2007 Oct 3; 27(40):10860-9.
    View in: PubMed
  17. Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, Lüscher B. GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci. 2007 Apr 4; 27(14):3845-54.
    View in: PubMed
  18. Fang C, Deng L, Keller CA, Fukata M, Fukata Y, Chen G, Lüscher B. GODZ-mediated palmitoylation of GABA(A) receptors is required for normal assembly and function of GABAergic inhibitory synapses. J Neurosci. 2006 Dec 6; 26(49):12758-68.
    View in: PubMed
  19. Qi JS, Yao J, Fang C, Luscher B, Chen G. Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures. J Physiol. 2006 Dec 1; 577(Pt 2):579-90.
    View in: PubMed
  20. Alldred MJ, Mulder-Rosi J, Lingenfelter SE, Chen G, Lüscher B. Distinct gamma2 subunit domains mediate clustering and synaptic function of postsynaptic GABAA receptors and gephyrin. J Neurosci. 2005 Jan 19; 25(3):594-603.
    View in: PubMed
  21. Keller CA, Yuan X, Panzanelli P, Martin ML, Alldred M, Sassoè-Pognetto M, Lüscher B. The gamma2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ. J Neurosci. 2004 Jun 30; 24(26):5881-91.
    View in: PubMed
  22. Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ, Smart TG, Lüscher B, Rees MI, Harvey RJ. The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci. 2004 Jun 23; 24(25):5816-26.
    View in: PubMed
  23. Sinkkonen ST, Lüscher B, Lüddens H, Korpi ER. Autoradiographic imaging of altered synaptic alphabetagamma2 and extrasynaptic alphabeta GABAA receptors in a genetic mouse model of anxiety. Neurochem Int. 2004 Jun; 44(7):539-47.
    View in: PubMed
  24. Lüscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004 Jun; 102(3):195-221.
    View in: PubMed
  25. Schweizer C, Balsiger S, Bluethmann H, Mansuy IM, Fritschy JM, Mohler H, Lüscher B. The gamma 2 subunit of GABA(A) receptors is required for maintenance of receptors at mature synapses. Mol Cell Neurosci. 2003 Oct; 24(2):442-50.
    View in: PubMed
  26. Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, Belzung C, Fritschy JM, Lüscher B, Mohler H. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci. 1999 Sep; 2(9):833-9.
    View in: PubMed
  27. Essrich C, Lorez M, Benson JA, Fritschy JM, Lüscher B. Postsynaptic clustering of major GABAA receptor subtypes requires the gamma 2 subunit and gephyrin. Nat Neurosci. 1998 Nov; 1(7):563-71.
    View in: PubMed
  28. Günther U, Benson J, Benke D, Fritschy JM, Reyes G, Knoflach F, Crestani F, Aguzzi A, Arigoni M, Lang Y, et al. Benzodiazepine-insensitive mice generated by targeted disruption of the gamma 2 subunit gene of gamma-aminobutyric acid type A receptors. Proc Natl Acad Sci U S A. 1995 Aug 15; 92(17):7749-53.
    View in: PubMed
  29. Hu YF, Lüscher B, Admon A, Mermod N, Tjian R. Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev. 1990 Oct; 4(10):1741-52.
    View in: PubMed
  30. Lüscher B, Mitchell PJ, Williams T, Tjian R. Regulation of transcription factor AP-2 by the morphogen retinoic acid and by second messengers. Genes Dev. 1989 Oct; 3(10):1507-17.
    View in: PubMed
  31. Williams T, Admon A, Lüscher B, Tjian R. Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. Genes Dev. 1988 Dec; 2(12A):1557-69.
    View in: PubMed
  32. Lüscher B, Schümperli D. RNA 3' processing regulates histone mRNA levels in a mammalian cell cycle mutant. A processing factor becomes limiting in G1-arrested cells. EMBO J. 1987 Jun; 6(6):1721-6.
    View in: PubMed
  33. Stauber C, Lüscher B, Eckner R, Lötscher E, Schümperli D. A signal regulating mouse histone H4 mRNA levels in a mammalian cell cycle mutant and sequences controlling RNA 3' processing are both contained within the same 80-bp fragment. EMBO J. 1986 Dec 1; 5(12):3297-303.
    View in: PubMed
  34. Lüscher B, Stauber C, Schindler R, Schümperli D. Faithful cell-cycle regulation of a recombinant mouse histone H4 gene is controlled by sequences in the 3'-terminal part of the gene. Proc Natl Acad Sci U S A. 1985 Jul; 82(13):4389-93.
    View in: PubMed
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