Bernhard Lüscher
Professor of Biology and
Professor of Biochemistry and Molecular Biology and Psychiatry
University Park, PA 16802
Research Interests
Structure, function and post-synaptic targeting of GABAA receptors
Research summary
Research in the Lüscher lab is concerned with understanding the structure, function and regulation of GABAergic inhibitory synapses and their receptors as well as their role in the etiology of neuropsychiatric disorders.
GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain and most of its function is mediated by so called GABA-A receptors. These are heteropentameric chloride channels that include a number of binding sites for clinically important drugs, most notably the benzodiazepines (BZs), which are widely used as anxiolytics, sedatives, sedatives, hypnotics, skeletal muscle relaxants, amnesics, anticonvulsants, and sedatives. Deficits in GABAergic transmission through GABA-A receptors are implicated in epilepsy, anxiety and mood disorders, schizophrenia, as well as some aspects of neurodegenerative disorders such as Huntington’s disease.
Differential expression and assembly of a multitude of structurally closely related subunits encoded by 19 distinct genes (alpha1-6, beta1-3, gamma1-3, etc.) leads to pronounced GABA-A receptor heterogeneity. Most types of GABA-A receptors consist of two alpha and two beta subunits, together with one gamma2 subunit. Our research aims to elucidate the molecular mechanisms that control the accumulation and dynamic regulation of GABA-A receptors in the plasma membrane and at synapses, and thereby regulate the known GABA-dependent and benzodiazepine-modulated behavioral brain states. In addition we are working on elucidating the neurochemical and neuroanatomical substrate of anxiety disorders and major depression. To address these issues we design mutant mouse models (global, cell type-specific and inducible), which we then study using molecular biology, cell biology, biochemistry, quantitative imaging, and behavioral pharmacology approaches, combined with stereotaxic manipulations of specific brain areas.
Figure 1. Schematic representation of a GABAergic inhibitory synapse depicting molecules involved in the dynamic modulation of synapse function (see Yuan and Luscher, 2007).
Figure 2. Brain areas and circuits that regulate the hypothalamus-pituitary-adrenal (HPA) axis and that are disregulated by GABAergic deficits leading to melancholic forms of major depression (see Shen et al. 2010).
Representative Publications
- Shen, Q., R. Lal, B. A. Luellen, J.C. Earnheart, A. M. Andrews and B. Lüscher (2010). GABAA receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity characteristic of melancholic depression. Biol Psychiatry (in press)
- 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 GABAA receptors. Mol. Cell. Neurosci. 38, 277-289.
- Deng L., J. Yao, C. Fang, N. Dong, B. Lüscher, 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.
- Yuan X and B. Lüscher (2007) Trafficking of postsynaptic GABAA receptors by receptor-associated proteins. In: GABA Receptors. S.Z. Enna and H. Mohler eds., Humana Press, Totowa, NJ.
- Earnheart JC., 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, 3845-3854.
- Qi J., J. Yao, C. Fang, B. Lüscher 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, B. Lüscher (2006). GODZ-mediated palmitoylation of GABAA 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. Lüscher (2005). Distinct γ2 subunit domains mediate clustering and synaptic function of postsynaptic GABAA receptors and gephyrin. J. Neurosci. 25, 594-603
