Cellular mechanisms of cortical function in vivo: We use two-photon calcium imaging in different areas of the mouse cortex (visual, auditory, sensorymotor) combined with targeted patch-clamp recordings to study electrical signaling and plasticity of specific types of neurons in behaviorally-defined conditions.
Cerebellar function and plasticity: We are interested in synaptic mechanisms, including the roles of mGlu receptors, TRPC channels, calcium signaling as well as in cerebellar sensory integration.
Dendritic signaling in vivo: Our major aim is the visualization and mapping of sensory-evoked signals on the level of individual synaptic inputs in defined neurons of the mouse cortex.
In vivo neurophysiology of Alzheimer’s disease. We focus on the impairments in synaptic signaling of cortical and hippocampal neurons in mouse models of Alzheimer’s disease.
Development of imaging technology: We develop and implement two-photon imaging devices with a high spatial and temporal resolution for the functional analysis of networks, cells and subcelullar compartments in vitro and in vivo.
The Misgeld lab studies axon changes in the healthy and in the sick nervous system of living animals. Axons are the long neuronal processes that form synapses and thus interconnect different parts of the nervous system. Obviously, to properly establish wiring in the brain, myriads of axons have to find their targets, or otherwise, axons that connect incorrectly need to be removed.
We are interested in the latter process – not only because such axon dismantling contributes fundamentally to brain development and to the adaptation of our neural circuits to the environment, but also because axons are highly susceptible to pathology. Many common neurological diseases are characterized by early loss of axonal connections – including motor neuron disease, spinal cord injury and multiple sclerosis, all of which we study. By better understanding axon dismantling in development and disease we hope to gain insight into what causes axons to disintegrate in disease.
We are interested in understanding how the vertebrate central nervous system (CNS) is assembled during development and exploit the retina, an accessible part of the CNS to do so. We use zebrafish, highly visual vertebrates that develop ex utero and are largely translucent during development, to study retinal development in real time in vivo. We probe the mechanisms that underlie the generation of diverse cell-types, their differentiation and integration into synaptic circuits. By combining genetic tools and in vivo time-lapse imaging, we can follow the developmental trajectories of cells from the time of their ‘birth’ to their arrival at their definitive locations, and their integration into the local circuitry.
We develop and use systems based on CCD-cameras and optic fibers for the fluorometric detection of population calcium signals. Such signals are generated by synchronous activity of large numbers of neurons organized in networks. Our recording systems are applied for studying basic brain function and the processing of sensory information as well as for the detection of impairments in mouse models of Alzheimer´s disease.
Another focus is the analysis of behavioral impairments in different transgenic mouse models such as models of Alzheimer´s disease or mice with cell-type specific knock-outs in cerebellar Purkinje cells. Furthermore we analyze the effects of drug treatments in our disease mouse models.
The main function of the cerebellum is the real-time control of movement precision and error-correction. Based on prior experience it improves motor behaviors because its activity is modified by learning. By controlling posture and muscle tone the cerebellum enables the execution of goal-directed movements with high spatial and temporal accuracy. The adaptation and optimization of the responsible circuits is the basis of procedural learning of complex movement sequences and conditioned responses. Many cortical sensory and motor areas send input into the cerebellum where they are processed with exceeding rapidity. These signals converge in the principle cerebellar neurons, the Purkinje cells. Most important, they represent the sole output of the cerebellar cortex. The firing pattern in Purkinje cell axons is the result of the entire signal processing and sensorimotor integration in the cerebellar cortex and thus critically determines cerebellar function. We study mechanisms of synaptic transmission, integration and plasticity at glutamatergic Purkinje cell synapses. For this purpose we use transgenic mouse lines that lack proteins with specific importance for cerebellar Purkinje cells. We investigate the functional role of these proteins and involved signaling cascades from the level of the single synapse or spine to their impact on animal behavior. We perform patch-clamp recordings on Purkinje cells in acute cerebellar slices in conjunction with confocal or two-photon imaging of intracellular Ca2+ signals in Purkinje cell dendrites and spines. These measurements are complemented with quantitative PCR analyses of single cell gene expression, immunohistochemical stainings and behavioral tests for the evaluation of motor performance of the transgenic mice.
We study the function and regulation of proteins – in particular proteases – involved in neurodegenerative diseases. The goal of our research is to better understand the mechanisms of neurodegeneration and to develop novel biomarkers and drug targets for prevention or treatment of neurodegenerative diseases, in particular Alzheimer’s disease.
We study how membrane proteins are proteolytically cleaved at the cell surface. This process is called Regulated Intramembrane Proteolysis (RIP) and is a basic cellular mechanism controlling the communication between cells and their environment. RIP was first discovered in Alzheimer’s disease, but contributes to numerous (patho)physiological processes. We study the molecular players - proteases, substrates and mechanisms - involved in RIP, in order to elucidate the biological function of this process and its connection to diseases. Recently, we have developed a novel proteomic method called SPECS which allows us to identify substrates and functions of RIP proteases. In another recent study we used lentiviral RNA interference and identified the metalloprotease ADAM10 as the long-sought alpha-secretase in primary neurons.
We have two Orbitrap mass spectrometers. We use quantitative mass spectrometry (label-free, dimethyl labeling, SILAC) to study proteins and their function in cells, tissues and whole organisms, such as zebrafish and mice. A focus is on proteins involved in neurodegeneration. Besides mass spectrometry, we use modern biochemical and cell biological methods, such as siRNA screens, primary neuronal and glial cultures, lentiviral transduction and confocal microscopy.