A5027802963- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Epilepsy research and treatment
- Metabolism and Genetic Disorders
- Neuroscience and Neural Engineering
- Neuroinflammation and Neurodegeneration Mechanisms
- Cell Image Analysis Techniques
- Neurological disorders and treatments
- Neural dynamics and brain function
- Diet and metabolism studies
- Single-cell and spatial transcriptomics
- CRISPR and Genetic Engineering
- Genetic Neurodegenerative Diseases
- Alzheimer's disease research and treatments
- Neuroscience of respiration and sleep
- Neurogenetic and Muscular Disorders Research
- Functional Brain Connectivity Studies
- Neurogenesis and neuroplasticity mechanisms
- Neurological and metabolic disorders
- Genetics and Neurodevelopmental Disorders
- Glycogen Storage Diseases and Myoclonus
- Viral Infections and Immunology Research
- Ion Transport and Channel Regulation
- Virus-based gene therapy research
Hertie Institute for Clinical Brain Research
2015-2025
University of Tübingen
2015-2025
Harvard University
2010-2018
Harvard Stem Cell Institute
2018
Herrenknecht (Germany)
2017
University of Southern Denmark
2017
University Children's Hospital Tübingen
2016
Universität Ulm
2005-2009
Technische Hochschule Ulm
2006-2009
Schneider Children's Medical Center
2008
Paroxysmal dyskinesias are episodic movement disorders that can be inherited or sporadic in nature. The pathophysiology underlying these remains largely unknown but may involve disrupted ion homeostasis due to defects cell-surface channels nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia echinocytosis,...
Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation analysis five-generation family co-occurrence of PED epilepsy (n = 39), suggesting that this combination represents entity. Based on whole genome linkage we screened SLC2A1, encoding glucose transporter blood-brain-barrier, GLUT1 identified heterozygous missense frameshift...
Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those onset before 4 years age represent a poorly studied subset. We screened 34 patients early-onset absence epilepsy for mutations in SLC2A1, the gene encoding GLUT1 glucose transporter. Mutations leading to reduced protein function were found 12% (4/34) patients. Two arose de novo, and two familial. These findings suggest deficiency underlies significant proportion epilepsy, which has both...
Retigabine (RTG) is an anticonvulsant drug with a novel mechanism of action. It activates neuronal KCNQ-type K<sup>+</sup> channels by inducing large hyperpolarizing shift steady-state activation. To identify the structural determinants KCNQ channel activation RTG, we constructed set chimeras using K<sub>v</sub>7.2 (<i>KCNQ2</i>) channel, which activated and cardiac K<sub>v</sub>7.1 (<i>KCNQ1</i>) not affected this drug. Substitution either S5 or S6 segment in respective parts led to...
Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as choreoathetosis/spasticity (DYT9) linked close to but not SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, addition PED, DYT9, 2) autosomal dominant forms...
<h3>Objective:</h3> To examine the role of mutations in <i>GABRB3</i> encoding β<sub>3</sub> subunit GABA<sub>A</sub> receptor individual patients with epilepsy regard to causality, spectrum genetic variants, their pathophysiology, and associated phenotypes. <h3>Methods:</h3> We performed massive parallel sequencing 416 a range epileptic encephalopathies childhood-onset epilepsies recruited additional from other research diagnostic programs. <h3>Results:</h3> identified 22 heterozygous...
Most of our knowledge on human CNS circuitry and related disorders originates from model organisms. How well such data translate to the remains largely be determined. Human brain slice cultures derived neurosurgical resections may offer novel avenues approach this translational gap. We now demonstrate robust preservation complex neuronal cytoarchitecture electrophysiological properties pyramidal neurons in long-term cultures. Further experiments delineate optimal conditions for efficient...
Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is main GABA transporter brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require delivery genes specific types neurons or areas likely during certain time points. In this issue JCI, Guo colleagues from Gray lab evaluated two promoters,...
Peripheral nerve hyperexcitability (PNH) is characterized by muscle overactivity due to spontaneous discharges of lower motor neurons usually associated with antibodies against voltage-gated potassium channels. PNH may also occur in combination episodic ataxia or epilepsy caused mutations K(V)1.1 K(V)7.2 Only one PNH-associated mutation has been described so far (R207W), a family both and neonatal seizures.PNH was video electromyography. The KCNQ2 gene sequenced channels were functionally...
Antiepileptic treatment of brain tumor patients mainly depends on the individual physician's choice rather than well-defined predictive factors. We investigated value defined clinical parameters to formulate a model risk estimations for subpopulations patients.We enclosed 650 > 18 years age who underwent surgery and included number data. Logistic regressions were performed determine effect sizes seizure-related factors develop prognostic scores occurrence preoperative early postoperative...
Pathophysiological investigation of CNS-related diseases, such as epilepsy or neurodegenerative disorders, largely relies on histological studies human post mortem tissue, tissue obtained by biopsy resective surgery and using disease models including animal models, heterologous expression systems cell culture based approaches. However, in general it remains elusive to what extent results model can be directly translated the brain, calling for strategies allowing validation even primary live...
Cortical spreading depression (CSD), a wave of depolarization followed by cortical activity, is pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke traumatic injury. To gain insight into the pathophysiology CSD, we generated mouse model for severe monogenic subtype aura, familial hemiplegic type 3 (FHM3). FHM3 caused mutations SCN1A, encoding voltage-gated Na+ channel NaV1.1 predominantly expressed inhibitory interneurons....
There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation SEEG electrodes, however, still challenging due to the anatomical location and complex functional segmentation both anteroposterior ventrodorsal (i.e., superoinferior) direction. While orthogonal approach (OA) shortest trajectory insula, it might insufficiently cover these networks. In contrast, anterior (AOA) or posterior oblique (POA) has potential full...
Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least decade before the onset clinical symptoms. Thus, understanding initiation propagation such is key for developing therapeutics to delay or halt disease progression.Alpha-synuclein (αS) inclusions were induced in long-term murine human slice cultures by seeded aggregation. An αS seed-recognizing antibody was tested blocking seeding and/or spreading lesions....
Epilepsy is considered as a network disorder of interacting brain regions. The propagation local epileptic activity from the seizure onset zone (SOZ) along neuronal networks determines semiology seizures. However, in highly interconnected regions such insula, association between SOZ and blurred necessitating invasive stereoelectroencephalography (SEEG). Normative connectomes on MRI data enable to link different symptoms lesion locations common functional network. present study applied...
Dendritic spines, small protrusions on neuronal dendrites, play a crucial role in brain function by changing shape and size response to neural activity. So far, depth analysis of dendritic spines human tissue is lacking. This study presents comprehensive spine morphology density using unique dataset from 27 patients (8 females, 19 males, aged 18-71) undergoing tumor or epilepsy surgery at three neurosurgery sites. We used acute slices organotypic slice cultures examine classifying them into...
Human cerebrospinal fluid (hCSF) has proven advantageous over conventional medium when culturing both rodent and human brain tissue. Increased excitability synchronicity, similar to the active state exclusively recorded in vivo, reported slice cell-cultures with hCSF as recording medium, indicates properties of not matched by artificial (aCSF) commonly used for electrophysiological recording. To evaluate possible importance using tissue, we compared general ex vivo tissue cultures during...