Lerche Lab

Experimental Epileptology

The goal of our research is to link the molecular mechanisms of mainly genetic, neurological diseases caused by disturbed neuronal excitability to their clinical symptoms and a personalized treatment. We are recruiting well-defined cohorts of patients with epilepsies and related disorders, searching for disease-causing genetic defects with modern sequencing techniques, particularly in ion channels or transporters, and analyzing their functional consequences to understand the pathomechanisms. A particular focus is
on finding and exploring new personalized therapies for genetic disorders. To study mechanisms of neuronal hyperexcitability on the molecular, cellular and network level, we use non-neuronal screening tools such as automated electrophysiology in oocytes and mammalian cells, neuronal expression systems including neurons derived from induced pluripotent stem cells and human brain slices, and gene-targeted mouse models.

Research projects
Members
Publications
Genetics and pharmacogenetics of epilepsy
Genetics and pharmacogenetics of epilepsy

Epilepsy affects up to 3% of people during their lifetime, with a genetic component playing a major pathophysiological role in almost 50% of cases. To analyze the genetic architecture of epilepsy we have initiated running national research networks (Treat-ION, DFG FOR-2715) and have initiated or been part of still ongoing European (ESF: EuroEPINOMICS, FP7: EpiPGX, ERANet Neuron:  SNAREopathies) and international (ILAE consortium on the genetics of complex epilepsies, Epi25, ILAE Genomics) networks confi ned to the recruitment of large cohorts of affected individuals and/or families and their genetic analyses. Major achievements in the last years were the prolongation of our DFG-Research Unit FOR 2715, entitled Epileptogenesis of Genetic Epilepsies, establishing Treat-ION, a BMBF-funded network for rare ion channel disorders in 2019 (prolongation pending), and founding ILAE Genomics to collect all available exomes sequenced in epilepsy patients wolrdwide. Important examples from recent studies are the identifi cation of 4-aminopyridine as a new and specifi c (‘precision’) treatment for a severe epilepsy with developmental problems of early childhood caused by mutations in KCNA2 (Hedrich, Lauxmann et al. Sci Transl Med 2021), the identifi cation of a new mechanism for migraine aura in an Scn1a mouse model (Auffenberg, Hedrich et al., JCI 2021), and very clear genotype-phenotype correlations with high relevance for clinical management for SCN8A related epilepsies (Johannesen, Liu et al., Brain 2021). A bioinformatic study in a large dataset of whole exomes from more than 8000 affected individuals with common epilepsies revealed that important functional gene groups, such as those of synaptic genes and ion channels / receptors, show specific patterns of enrichment of pathological variants compared to controls in generalized vs. focal epilepsies (e.g. affecting inhibitory vs. excitatory pathways), and also show that signals from common and rare variants converge and contrast in generalized vs. focal epilepsies.

Functional investigations of genetic defects in ion channels
Functional investigations of genetic defects in ion channels

With the BMBF-funded Treat-ION consortium on Neurological Ion Channel and Transporter Disorders we focus on therapeutic studies in cellular, animal and human models, which are complemented by in silico searches for new treatments, better predictions for the functional consequences of mutations for therapeutic purposes and cellular drug screens. The use of approved and available ‘repurposed’ drugs such as 4-aminopyridine is a a specific goal to enable precision treatment. Our findings are directly delivered to patients through molecular therapeutic boards attached to the German academy of rare neurological diseases (DASNE) and the centers for rare diseases (ZSEs) in Baden-Württemberg and through a structured process for drug repurposing. Functional implications of selected mutations are examined in neuronal expression systems, such as transfected murine primary neurons, in utero electroporated neurons and genetically altered animal models carrying a human mutation (so-called “humanized mouse models”). The advantage of both in utero electroporated neurons and gene-targeted mouse models is that altered channels can be studied in their natural environment and additionally, the consequences on intrinsic neuronal properties and network activity can be studied using single cell patch clamp, extracellular recording or multielectrode array (MEA) techniques. We perform 256 electrode MEA recordings and high-resolution electrical imaging (CMOS with 4000 electrodes) to analyze single cell compartments and neuronal network activity in brain slices of transgenic animals and study network dysfunction of our mouse models in vivo together with O. Garaschuk (Inst. Neurophysiology) using Ca2+ imaging in the frame of the DFG Research Unit. To gain insight into the exact mechanisms as to how epilepsy develops as a consequence of a genetic defect, we investigate brain region- and time-specific RNA expression using single cell RNA sequencing in distinct neuronal subpopulations in mouse models.

Induced pluripotent stem cells as epilepsy models
Induced pluripotent stem cells as epilepsy models

Since human brain tissue is a limited resource in neuroscience research, we are additionally generating neurons from induced pluripotent stem cells (iPSCs). These represent an attractive, albeit simplified, alternative of a human model system to study diseases of the nervous system.

By reprogramming patient-specific fibroblasts into pluripotent stem cells and subsequently overexpressing specific transcription factors, we can specifically generate excitatory and inhibitory cortical neurons. In subsequent functional studies, the disease mechanism of individual patients can be investigated taking into account their unique genetic background. We investigate network activity using a multiwell-MEA system as well as single cell activity by patch clamp measurements. By this, we were already able to show that developmental electrophysiological activity patterns in iPSC-derived neurons are comparable to those in humans and animals (Rosa et al., Stem Cell Rep 2020). Current projects include electrophysiological analysis of patient-specific iPSC neurons carrying pathological mutations in genes encoding ion channels (KCNA2, KCNH1) or synaptic proteins (STX1B).

Human brain slices cultures
Human brain slices cultures

As another human model system, we are using human slice cultures which can be maintained for up to four weeks with good neurophysiological properties when human cerebrospinal fluid (CSF) is used as culture medium. The use of ex vivo brain slices derived from adult human neurosurgical-resected tissue allows to probe electrophysiological properties at single cell and network level (Schwarz et al., Sci Rep 2017). We demonstrated robust preservation of neuronal cytoarchitecture and electrophysiological properties of human pyramidal neurons. Further experiments delineate the optimal conditions for efficient viral transduction of cultures, enabling ‘high throughput’ fluorescence-mediated 3D reconstruction of genetically targeted neurons, and demonstrate feasibility of long term live cell imaging of human cells in vitro.


 
Name
Research Group
Phone
Email
 Jacqueline Bahr
Jacqueline BahrPhD Student
Experimental Epileptology

+49 (0) 7071
2-981983

 
 Marie Bellet
Marie BelletPhD Student
Experimental Epileptology

+49 (0)7071-
29-81914

 
Dr. med. Christian Bosselmann
Dr. med. Christian BosselmannPhysician
Experimental Epileptology


 
 Yvonne Braendle
Yvonne BraendleSecretary
Experimental Epileptology

+49 (0) 7071
29-80442

 
 Elisabeth Brand
Elisabeth BrandPhD Student
Experimental Epileptology

+49(0)7071-
29-81914

 
 Hanna Brüggemann
Hanna BrüggemannMedical Student
Experimental Epileptology

+49 (0)7071-
29-81914

 
 Hayri Can Calap
Hayri Can CalapMedical Student
Experimental Epileptology


 
 Patricia Cseh
Patricia CsehPhD Student
Experimental Epileptology

+49 (0)7071-
29-81914

 
 Maryam Erfanian Omidvar
Maryam Erfanian OmidvarPhD Student
Experimental Epileptology

+49 (0) 7071
29-87639

 
 Albina Farkhutdinova
Albina FarkhutdinovaPhD Student
Experimental Epileptology

+49 (0)7071
29 81914

 
 Carolin Fischer
Carolin FischerPhD Student
Experimental Epileptology

+49 (0) 7071
2981914

 
Dr. Zofia Fleszar
Dr. Zofia FleszarPhysician
Experimental Epileptology

+49(0)7071-
29-85247

 
 Ana Fulgencio Maisch
Ana Fulgencio MaischTechnical Assistant
Experimental Epileptology

+49 (0) 7071
29-87638

 
 Felix Gsell
Felix GsellPhysician
Experimental Epileptology

+49 (0)7071-
29-81921

 
 Shaimaa Haiba
Shaimaa HaibaPhD Student
Experimental Epileptology

+49 (0)7071
29-81983

 
Dr. Ulrike Hedrich-Klimosch
Dr. Ulrike Hedrich-KlimoschPostdoc
Experimental Epileptology

+49 (0) 7071
29-81984

 
 Madeleine Held
Madeleine HeldPhD Student
Experimental Epileptology

+49 (0)7071-
29-81921

 
 Christian Hengsbach
Christian HengsbachStudy Assistant
Experimental Epileptology

+49 (0) 7071
29-86525

 
 Stefano Iavarone
Stefano IavaronePhD Student
Experimental Epileptology

+49 (0) 7071
2981914

 
 Myvledin Kameraj
Myvledin KamerajTechnical Assistant
Experimental Epileptology

+49 (0)7071-
29-87638

 
 Josua Kegele
Josua KegelePhysician
Experimental Epileptology

+49 (0) 7071
29-86588

 
 Sabrina Kreiser
Sabrina KreiserSecretary
Experimental Epileptology

+49 (0) 7071
29-80442

 
 Caroline Kurth
Caroline KurthMedical Student
Experimental Epileptology

+49 (0)7071-
29-81921

 
 Robert Lauerer-Braun
Robert Lauerer-BraunPhysician
Experimental Epileptology

+49 (0)7071-
29-81983

 
 Nikolas Layer
Nikolas LayerPhD Student
Experimental Epileptology

+49 (0) 7071
29-80440

 
Prof. Dr. Holger Lerche
Prof. Dr. Holger LercheHead of Department
Experimental Epileptology

+49 (0) 7071
29-80442

 
Dr. Yuanyuan Liu
Dr. Yuanyuan LiuPostdoc
Experimental Epileptology

+49 (0) 7071
29-81921

 
 Heidi Loeffler
Heidi LoefflerTechnical Assistant
Experimental Epileptology

+49 (0) 7071
29-81922

 
 Hang Lyu
Hang LyuPhD Student
Experimental Epileptology

+49 (0) 7071
29-80440

 
 Daniela Miely
Daniela MielyPhysican
Experimental Epileptology

+49 (0) 7071
29-80440

 
 Lena Mittelstraß
Lena MittelstraßPraktikantin
Experimental Epileptology


 
 Peter Müller
Peter MüllerPhysician
Experimental Epileptology

+49 (0) 7071
29- 81968

 
 Lorenz Over
Lorenz OverMedical Student
Experimental Epileptology

+49 (0)7071
29-81914

 
 Filip Rosa
Filip RosaPhysician
Experimental Epileptology


 
Prof. Dr. Sigrid Schuh-Hofer
Prof. Dr. Sigrid Schuh-HoferPhysician
Experimental Epileptology

+49(0)7071
29- 80442

 
Dr. Niklas Schwarz
Dr. Niklas SchwarzPhysician
Experimental Epileptology

+49 (0) 7071-
29-81914

 
 Hannah Schwarz
Hannah SchwarzMedical Student
Experimental Epileptology


 
 Sascha Steiner
Sascha SteinerPhD Student
Experimental Epileptology

+49 (0)7071
29-81921

 
 Sarah Streicher
Sarah StreicherPhD Student
Experimental Epileptology

+49 (0) 7071-
29 81914

 
 Oleg Vinogradov
Oleg VinogradovPostdoc
Experimental Epileptology

+49 (0)7071-
29-80440

 
 Nan Zhang
Nan ZhangMedical Student
Experimental Epileptology

+49 (0) 7071
29-81914

 

Selected Publications

 

Müller P*, Takacs DS*, Hedrich UBS, Coorg R, Masters L, Glinton KE, Dai H, Cokley JA, Riviello JJ, Lerche H#, Cooper EC#. KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine. Ann Clin Transl Neurol. 2023 Feb 15.

 

Krüger J, Schubert J, Kegele J, Labalme A, Mao M, Heighway J, Seebohm G, Yan P, Koko M, Aslan-Kara K, Caglayan H, Steinhoff BJ, Weber YG, Keo-Kosal P, Berkovic SF, Hildebrand MS, Petrou S, Krause R, May P, Lesca G, Maljevic S, Lerche H. Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies. EBioMedicine. 2022 Oct;84:104244. doi: 10.1016/j.ebiom.2022.104244.

 

Johannesen KM*, Liu Y*, Koko M, Gjerulfsen CE, Sonnenberg L, Schubert J, Fenger CD, Eltokhi ARannap M, Koch NA,Lauxmann S, Krüger J, Kegele J, (…),Hedrich UBS, Benda J, Gardella E,Lerche H#, Møller RS#. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain 2021:awab321.


Auffenberg E*, Hedrich UB*, Barbieri R*, Miely D*, Groschup B, Wuttke TV, (…), Pusch M, Dichgans M, Lerche H, Gavazzo P#, Plesnila N#, Freilinger T#. Hyperexcitable interneurons trigger cortical  spreading depression in an Scn1a migraine model. J Clin Invest 2021;131:e142202.


Hedrich UBS*, Lauxmann S*, (…), Bosselmann C, Schwarz N, Fudali M, Lerche H. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Sci Transl Med 2021;13:eaaz4957.


Koko M, Krause R, Sander T, Bobbili DR, Nothnagel M, May P,Lerche H; Epi25 Collaborative. Distinct gene-set burden patterns underlie common generalized and focal epilepsies. EBioMedicine 2021;72:103588.


Rosa F, Dhingra A, Uysal B, Mendis GDC, Loeffler H, Elsen G, Mueller S, Schwarz N, Castillo-Lizardo M, Cuddy C, Becker F, Heutink P, Reid CA, Petrou S, Lerche H#, Maljevic S#. In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment. Stem Cell Reports 2020;15:22-37.

 

Schwarz N, Hedrich UBS, Schwarz H, P A H, Dammeier N, Auffenberg E, Bedogni F, Honegger JB, Lerche H, Wuttke TV, Koch H. Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Sci Rep. 2017 Sep 25;7(1):12249.

 

Research Group LeaderDirector of the Department
Prof. Dr. Holger Lercheholger.lerche@uni-tuebingen.deAddress

Hertie Center of Neurology
Hertie Institute for Clinical Brain Research
Department Neurology and Epileptology

Hoppe-Seyler-Straße 3
72076 Tübingen

Phone: +49 (0)7071 29-80442
Fax: +49 (0)7071 29-4488

Office

Sabrina Kreiser
Yvonne Brändle
Phone: +49 (0)7071 29-80442
Fax: +49 (0)7071 29-4488
sekretariatne5.HL@med.uni-tuebingen.de

Lab Management

Heidrun Löffler
Phone: +49 (0)7071 29-81922
heidi.loeffler@medizin.uni-tuebingen.de