Numerous self-organized rhythms are present in the brain in distinct cortical networks, in particular in those implicated in cognitive functions. One of these rhythms is the theta rhythm which represents one of the most prominent synchronous signals of the mammalian brain. This rhythm can be recorded across several brain regions and is very pronounced in the hippocampus. There is evidence that this rhythm is involved in packaging and segmentation of neuronal information. Thereby, it contributes to information processing in the brain and to the organization of cognitive processes such as learning and memory. The medial septum (MS) has an essential role for the generation of hippocampal theta rhythm. My group is interested in understanding how HCN channels and other cation channels in pacemaker neurons of the medial septum (MS) drive the hippocampal theta rhythm. We also investigate how other rhythms in the brain (circadian rhythm, rhythms in the thalamocortical system) are generated and how changes in these processes lead to epilepsy and other diseases of the central nervous system. This work is currently funded in the CRC 870 „Assembly and Function of Neuronal Circuits“.

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. In fact, more people die annually from CVDs than from any other reason. Current calculations predict that by 2030, 23,6 million people will die from CVDs. It is therefore essential to understand the underlying mechanisms of these CVDs and to develop novel cardioprotective and therapeutic strategies to halt this dramatic development. The performance of the cardiac muscle is controlled by the spontaneous activity of pacemaker cells in the sinoatrial node (SAN) which generate the heartbeat. Importantly, the heart rate (HR) is a prognostic factor for cardiac morbidity and mortality. Our group investigates the role of HCN channels and other ion channels for the generation of a regular and well-coordinated HR. In general, pacemaking requires functional interactions between individual pacemaker cells within the SAN itself (a process called „basis“ entrainment), between SAN cells and regulating neurons of the autonomic nervous system (neuronal entrainment) and finally between SAN cells and the hormone system (humoral entrainment). Our hypothesis is that in particular cAMP-dependent regulation of HCN4 channels contributes to the neuronal and humoral entrainment and that HCN1 and other ion channels are responsible for the “basis“-entrainment, the actual synchronization process within the sinoatrial node itself (Fenske et al. Circulation 2013). 

Using a series of genetic knock-out and knock-in models, reporter as well as sensor lines my group aims at investigating the role of these HCN channels as well as additional cation channels and their regulation for the three entrainment processes. We also investigate how the intracardiac nervous system (ICNS) regulates the spontaneous heart beat and contractility. The ICNS, like other extracranial neuronal networks located in distinct organs, operates independently of the autonomic and the central nervous system. For our projects, we use state-of-the-art methods such as patch clamp, confocal FRET microscopy (Direnberger et al. Nature communications 2012), confocal Ca2+ and voltage imaging, optogenetics, ECG telemetry (Fenske et al., Nature Protocols 2016), cardiac catheterization based in vivo electrophysiological and pressure analysis as well as optic mapping to visualize the spread of electrical excitation throughout the heart with ultra-high time resolution (10-30.000 Frames/s) using voltage-sensitive dyes. The project is funded by the DFG

Trafficking of intracellular membrane vesicles (endosomes and lysosomes) involve the formation, fusion and fission of vesicles as well as their tight interaction with filaments of the cytoskeleton and associated motor proteins. These processes are fundamental for life, occur in every cell of the body and collectively regulate intracellular logistics, signalling and intra- and intercellular communication. Defects in endosomal trafficking lead to various diseases such as metabolic disorders, infection, tumor development and growth as well as neurodegenerative and cardiovascular diseases. The membranes of intracellular vesicles of the endo-lysosomal system contain a variety of ion channels which control ion homeostasis (including pH control) of the vesicular lumen and the peri-vesicular microenvironment. Our group is particularly interested in two pore channels (TPCs), TRPML1,2,3 and TRPM2 channels which are localized in endo-lysosomal vesicles. These channels form a subgroup within the TRP (transient receptor) channel superfamily. In order to characterize the function of these channels in their specific intracellular vesicle system, we developed the endo-lysosomal patch clamp technique. Using this and other methods, we identified the role of TPC2 channels for hepatic and systemic lipoprotein and cholesterol homeostasis, for endo-lysosomal trafficking and cytosolic release of the Ebola virus, as well as for hair pigmentation. In addition, we discovered several other novel functions for TPCs, including their role for the acrosome reaction in sperm, cancer cell migration, or trafficking of bacterial toxins, e.g. cholera-toxin. Currently, we are focussing on the role of TPCs, TRPML channels and other ion channels in the brain and cardiovascular system. The project is currently funded by TRR/CRC152, “Maintenance of body homeostasis by transient receptor potential channel modules".

Another focus of my group is the development and utilization of novel and highly innovative methods for cardiac in vivo and in vitro physiology, for confocal Ca2+- and voltage imaging, for endo-lysosomal patch clamp and for quantitative FRET microscopy. Part of these methods have been developed in my group and were published in Science Signaling, Nature communications, Circulation as well as in three recent papers in Nature Protocols. For these methods we regularly organize workshops within the TRR/CRC152, dealing with FRET (title: “FRET –“seeing” molecular interactions”), dealing with the endo-lysosomal patch clamp method (title: “whole-endosomal patch-clamp approach”) and focusing on single channel recordings (title: “ion channels of excitable membranes 2016”).