Expertise and current research performed: The group has a long-standing experience with structure-function analysis and the gating properties of ion channels using molecular biological and electrophysiological techniques. In particular, the group has been functionally characterising disease-causing mutations in ion channel disorders. They recently described a novel epilepsy gene, CLCN2, for the common idiopathic generalized epilepsies (cooperation with Armin Heils, SP1). Exploring novel pharmacotherapies and the role of affected ion channels in neurons are other fields of interest in the group. They have a clinical and genetic expertise in phenotyping and genotyping of inherited neurological diseases, in particular of idiopathic epilepsy syndromes, and in the diagnosis and treatment of the epilepsies. The current research focus is on the genetics and pathophysiology of idiopathic epilepsies. Whereas most of their previous and a lot of ongoing studies have been carried out in heterologous expression systems, the group is now exploring the functional implications of epilepsy-associated mutations in neurons and determining the specific roles of affected channels in the brain. These studies involve the cellular and subcellular localization, targeting mechanisms and functional analyses of wild type and mutant channels in cultured neurons and brain slices using immunohistochemistry, imaging of fluorescent fusion proteins and electrophysiology. In addition, the group is working on molecular pharmacological mechanisms of antiepileptic drugs acting on ion channels and on the characterisation of ion channels in stem cells.

Facilities/Equipment: The Depts. of Neurology and Applied Physiology and the Center for Clinical Research at the University of Ulm are equipped with patch clamp facilities for cells in culture and brain slices combined with fluorescence imaging, two-electrode voltage clamp of oocytes, all molecular biological, cell culture and histological facilities for mutagenesis and cloning, mammalian and primary neuronal cultures and immunohistochemistry, and confocal fluorescence microscopy.

Personnel involved in the project

Principal investigator: Holger Lerche (M). PD Dr. med. Degrees: MD, ‘Habilition’ in Neurology, Neurologist, Epileptologist. Actual positions: Heisenberg fellow of the German Research Foundation (DFG) (actual sabbatical at UCL Institute of Neurology, London, 6-12/2005); Assistant Professor, Consultant Neurologist and Head of Epileptology at the Neurological Clinic, University of Ulm; Head of an Experimental Research Group at the Depts. of Neurology and Applied Physiology, University of Ulm. Working in the field since 1991. Research interests: Ion channel disorders, genetics and pathophysiology of idiopathic epilepsies, ion channel gating mechanisms and pharmacology, localization and targeting of ion channels in neurons, electrophysiology of stem cells

Snezana Maljevic (F). Dr. biol. hum., Dipl. biol. Degrees: PhD in life sciences, Diploma in Biology. Actual position. Postdoctoral fellow/research assistant at the Dept. of Experimental Neurology, University of Ulm. Working in the field since 2001. Research interests are: Gating mechanisms, pathophysiology, localization and targeting of GABA_A receptors, ClC-2 channels and KCNQ channels. Mariana Oana Popa (F). Dr. biol. hum., Dipl. phys. Degrees: PhD in life sciences, Diploma in Physics. Actual position. Postdoctoral fellow/research assistant at the Dept. of Applied Physiology, University of Ulm. Working in the field since 2001. Research interests are: Structure-function analysis and gating mechanisms of voltage-gated Na⁺ and Ca²⁺ channels and their functional role in neurons; ion channels in stem cells. Yvonne Weber (F). Dr. med. Degrees: MD, Neurologist, Epileptologist at the Neurological Clinic of the University of Ulm, postdoctoral fellow/research assistant at the Dept. of Experimental Neurology, University of Ulm. Working in the field since 2000. Research interests are: Phenotyping and genetics of epilepsies and other inherited neurological disorders, localization of ion channels in the brain. Thomas Wuttke (M). Dr. med. Degrees: MD. Actual position. Resident and postdoctoral fellow/research assistant at the Dept. of Neurology, University of Ulm. Working in the field since 2002. Research interests are: Molecular pharmacological mechanisms of novel anticonvulsive drugs acting on ion channels, functional characterization of stem cells. Yunxiang Liao (F). Degrees: MD, Master of Public relations. Research interests: Gating and pathophysiology of neuronal voltage-gated ion channels. Simone Schubert (F). Degrees: Diploma in Biology. Research interests: Localization of neuronal voltage-gated ion channels. Sigrid Bail (F). Working in the field since 1998. Research interests: molecular biology (mutagenesis and cloning), immunohistochemistry, cell culture. Dragica Blazevic (F). Working in the field since 2000. Research interests: cell culture, immunohistochemistry, molecular biology, functional assays

Recent relevant publications/patents

1.        Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H. (2005). The new anticonvulsant Retigabine favors voltage-dependent opening of the K_v7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharm 67:1009-17.

2.        Lerche H, Weber YG, Jurkat-Rott K, Lehmann-Horn F. (2005). Ion channel defects in idiopathic epilepsies. Curr Pharm Des 11:2737-52.

3.        Haug K, Warnstedt M, Alekov AK, Fahlke C, Lerche H^§, Heils A^§. (2003). Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 33:527-32 ^§corresponding authors.

4.        Alekov AK, Rahman MM, Mitrovic N, Lehmann-Horn F, Lerche H. (2000). A Na⁺ channel mutation causing epilepsy in man exhibits subtle defects in fast inactivation and activation in vitro. J Physiol 529:533-9.

5.        Lerche H, Biervert C, Alekov AK, Steinlein OK. (1999). A reduced K⁺ current due to a novel mutation in KCNQ2 causes neonatal convulsions. Ann Neurol 46:305-12