The Kreutz Lab
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Research


Research

Research in NPlast in Magdeburg and DOF in Hamburg is concerned with fundamental questions on how synapses communicate with the nucleus, how gene activity-dependent gene expression feeds back to synaptic function and how this is related to the formation of a cellular engram and last but not least how the nanoscale organization of the synapse determines functional properties in the context of learning and memory. We use a multi-disciplinary approach with studies ranging from single molecules to in vivo animal experimentation. We also address translational aspects where we try to understand whether the processes that we investigate might be relevant for disease. The Leibniz Group 'Dendritic Organelles and Synaptic Function' at the ZMNH in Hamburg investigates how microsecretory systems and organelles in neurites are involved in synaptic function. We are interested in organelles like autophagosomes, lysosomes, and Golgi satellites and their local contribution to neurotransmission.

In the past decade several studies have proposed mechanisms of activity dependent transport of synaptic proteins to the nucleus. NMDA-receptors play a crucial role in plasticity-related gene expression and NPlast has shown that the NMDAR complex, which consists of about 100 different proteins, is a rich source of synapto-nuclear protein messenger. In total five of these proteins (Jacob, Abi-1, RNF10, Prr7 and Rack1) were identified by us and our collaborators in various screens and the work done on these proteins has led to the concept that different NMDAR signals induce the nuclear translocation of different proteins. Thus, we believe that proteins that directly interact with NMDAR subunits can be transported to the nucleus. Following nuclear import these proteins associate with transcription factor complexes and can induce sustained changes in gene expression. This mechanism allows for encoding of signals at the site of origin and decoding in the nucleus. Nuclear import of synapto-nuclear messenger proteins can keep the nucleus informed about the number of newly inserted NMDAR, their synaptic/extrasynaptic localization, the NMDAR subtype activated, NMDAR-dependent LTP/LTD and so on.

Dendritic spines represent the basic cellular unit for memory storage. Alterations in synaptic strength require an intimate link between functional and structural plasticity. The latter one is based on the unique cytoskeletal organization of differentially arranged actin filaments. Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling (see below). Another important role for the organization of the spine synapse is played by an electron-dense structure beneath the postsynaptic membrane termed postsynaptic density (PSD). The PSD contains specialized and elaborate molecular scaffolds that link synaptic neurotransmission to various signaling cascades and the actin cytoskeleton. Molecular and ultrastructural analysis of the PSD has led to the identification of several hundred PSD constituents and to the notion that the PSD is a multi-layered complex, composed of membrane molecules, primary scaffolding molecules and higher order scaffolding molecules that bind sub-complexes and cytoskeletal components into even more elaborate structures. In the last years we contributed to the analysis of structure, assembly and molecular dynamics of the PSD. Current projects also deal with translational aspects like synaptic insulin resistance in the metabolic syndrome (Funded by Europäische Struktur- und Investitionsfonds / Foundation; Forschungsverbund Autonomie im Alter).

NPlast has identified a group of CaM-like Ca2+-sensor proteins that we call nCaBPs (neuronal Calcium-Binding proteins). Research is focused on the three nCaBPs Caldendrin, Calneuron-1 and -2. We are interested how neuronal calcium signals are decoded by these calcium sensors and translated into cellular responses. Calneurons are transmembrane Calmodulin-like Ca2+-sensors that play role in Golgi-to-plasma-membrane trafficking. We are currently investigating other cellular functions, which is of particular relevance since the human CALN1 gene is a schizophrenia risk gene. Caldendrin has a unique bipartite structure with a highly basic and proline-rich N-terminus and an EF-hand containing C-terminus. The protein is enriched in the postsynaptic density and we try to learn more about its role in dendritic spine dynamics.

Changes in the expression or functional properties of ion channels at the level of the axon initial segment, where action potentials are initiated, or modifications in dendritic excitability, affecting the integration of synaptic inputs, can strongly influence the input-output function of a neuron rendering it more or less excitable. The team around Jeffrey seeks to understand the contribution of low-voltage activated calcium channels and potassium channels to intrinsic excitability in mature granule cells of the dentate gyrus. Mature granule cells show also a strong dendritic attenuation of voltage signals, making the contribution of individual synaptic inputs to action potential initiation small. Therefore, non-synaptic forms of plasticity may play a more dominant role in this particular cell type than in other hippocampal neurons. Along these lines we have recently found that mature granule cells can increase their ability to fire action potentials in response to synaptic stimulation after weak but physiologically relevant conditioning protocols that did not even elicit any synaptic potentiation. Those changes are related to modifications in intrinsic dendritic excitability, most probably by modulation of A-type potassium channels allowing a more efficient voltage transfer from dendrites to the soma. We are currently investigating the molecular mechanisms supporting these excitability changes.

In recent years it has become apparent that a satellite microsecretory system might exist in neuronal processes that allows for local synthesis and processing of synaptic transmembrane proteins. In recent work we have shown the presence of a widespread ER-ERGIC-Golgi satellite-retromer microsecretory system in all dendrites of pyramidal neurons through which a broad spectrum of synaptic transmembrane proteins might pass and even recycle. We currently study which proteins pass through this system, characterize the organelles involved and try to address the functional implications of autonomous local control of protein processing and recycling. Some reports have indicated that hybrid organelles might exist in neurons but very little is known about their assembly and their functional role. Apart from Golgi satellites we also investigate aspects of amphisome signaling but also of unconventional roles of lysosomes in neurons.