Functional and molecular neurogenetics of paroxysmal neurological brain disorders

Principal investigator
Prof.dr. Arn M.J.M. van den Maagdenberg

Our group investigates functional and molecular neurogenetic aspects of various paroxysmal neurological brain disorders, with a primary focus on migraine, a severe, common, brain disorder with a clear genetic component. Our main research goal is to dissect pathological mechanisms involved in the onset of attacks and identify novel (prophylactic) drug targets for improved treatment. In addition, our research activities focus on understanding specific triggering pathways and the main co-morbidities of migraine, i.e. epilepsy, depression and stroke. In close collaboration with the department of Neurology we generated a web-based patient recruitment system LUMINA (acronym for Leiden University Medical Centre Migraine Neuro Analysis), which now contains over 6,000 patients. Of close to 4,000 we have genomic DNA and detailed genetic information that is used for genetic analyses. For several hundred patients we also have plasma, cerebrospinal fluid and/or neuro-imaging information. 

Historically, part of our genetic research focused on the identification of genes for familial hemiplegic migraine, a severe subtype of migraine with aura. FHM genes point towards a mechanism of disturbed ion transport and neurotransmitter homeostasis. For the identification of gene variants for the common forms of migraine, we have been at the forefront of genome-wide association studies (GWAS), in international collaborative efforts, taking advantage of our large LUMINA patient database. Current results from GWAS highlight the importance of neurotransmitter and vascular mechanisms in migraine pathophysiology. Nowadays, next-generation sequencing in patient samples of monogenic and complex episodic neurological disorders (i.e. migraine and epilepsy) has become more prominent in our research activities. To ensure optimal translational impact of our research, we have generated transgenic mouse models, many of them expressing gene mutations we had identified in patients. Our neurobiological, neuroimaging and neurobiochemical research platforms will help us better understand migraine and its relation to other brain diseases. To this end we have operational a highly integrated multidisciplinary platform of genetics, biochemistry, -omics and state-of-the-art electrophysiology (including several dedicated awake electrophysiology and optogenetics setups). For better translation to the clinic, recently, we have begun exploiting the unique possibilities of induced pluripotent stem cells (iPSCs), derived from patients with paroxysmal disorders, that can be differentiated in neuronal, glial and vascular cells. To this end, in close collaboration with researchers from the LUMC Stem Cell Facility, Human Genetics and Neurology, we generated the LUMC Neuro-iPSC lab dedicated for brain studies.

Within the LUMC, we have intensive collaborations with the Department of Neurology and various Departments. Outside the LUMC we have many collaborations with national and international research groups.

Figure: Characteristics of optogenetically induced CSD in freely behaving Thy1/ChR2-YFP mice. (A) Combined DC-potential and multi-unit activity (MUA) recordings in the visual (V1) and motor (M1) cortex with S1 laser Doppler flow measurements during V1 460-nm (blue) light stimulation and CSD. Arrival of the CSD wave front at the intracortical electrodes is characterized by a negative deflection of DC-potential coinciding with a peak of intense neuronal firing (i.e. increased MUA) that is followed by neuronal silencing.  (B) Comparable CSD threshold characteristics were found in a second starting 20 min after the first CSD). (C) Propagation rate for the second CSD was reduced, (D) V1 MUA response during the first photostimulation pulse of the second threshold measurement. (E) Stable CSD threshold during seven repetitive daily CSD threshold assessments. 

Section leaders epilepsy 
Prof.dr. Arn M.J.M. van den Maagdenberg, Dr. Else A. Tolner

A specific focus is research in epilepsy, also because it is an important comorbidity of migraine. Not only have we identified various genes for specific forms of epilepsy (e.g. myoclonic epilepsy and focal epilepsy), but also we have shown that various gene mutations in core FHM genes have epilepsy as a clinical symptom. The close, but at present hardly understood, association of migraine and epilepsy is shown and studied in our transgenic mouse models. The most striking example, is a transgenic migraine mouse model that presents with sudden unexpected death in epilepsy for which we have unravelled neurobiological mechanisms.