Bernhard Luscher

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 that are known to modulate higher order brain function as the targets of several classes of clinically and therapeutically important psychoactive drugs, most notably the benzodiazepines (Valium, Xanax, Versed, etc).

A first area of interest are 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, and determining how these contribute to dynamic functional modulation of synapses. In particular, 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).

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.