The lab is interested in molecular and cellular mechanisms that control plasticity of neurotransmitter release and presynapse-to-nucleus signalling and their role in normal brain function and in disease.
Our publications on PubMed.
Assembly and dynamics of presynaptic release sites
Dynamic organisation of presynaptic voltage-gated calcium channels
Together with collaborating groups we revealed important role of bassoon in the positional priming of voltage-gated calcium channels (VGCC), i.e. their exact in respect to release sites (Frank et al., 2010; Hallermann et al., 2010; Jing et al., 2013). We demonstrated a key role of direct interaction of bassoon with RIM-binding protein (RBP) in this process (Davydova et al., 2014). RBP has been shown previously to link VGCC and an important regulator of SV priming Rab-3 interacting molecule (RIM). In contrast to RIM, which is the main VGCC-recruiting molecule at release sites and which interacts and recruits both main types (Cav2.1 and Cav2.2) of presynaptic VGCC, Bassoon regulates specific recruitment of Cav2.1 at conventional synapses (Davydova et al., 2014).Since the exact positioning of VGCC towards docked SVs critically regulates the presynaptic release probability it is likely that modulation of this step importantly shapes the presynaptic short-term plasticity. In line with this assumption, we could recently demonstrate importance of scaffold-VGCC interaction for molecular dynamics and clustering of VGCC and eventually for presynaptic short term plasticity (Heck et al., 2019). In this study we expressed splice variants of Cav2.1 differing in their binding to presynaptic scaffolds and monitored their molecular mobility and effect on neurotransmission using super resolution imaging (sptPALM) of VGCC, genetic sensors of neurotransmission and patch-clamp electrophysiology in living cells.
Regulation of SV recyling
As an additional effect of bassoon deletion, electrophysiological recordings revealed decrease in the size of readily releasable pool of vesicles in multiple types of synapses as well as defects in the release sites reloading during high frequency stimulation in cerebellar mossy fiber to granule cell synapses (Frank et al., 2010; Hallermann et al., 2010; Jing et al., 2013). In a running project that addresses the molecular basis of this phenotype using imaging of SV recycling in cultured neurons. Here, we identified multiple functional interactions of bassoon with synaptic kinases and phosphatases, which seems to critically influence the presynaptic short-term and homeostatic plasticity via regulation of SV recycling at several entry sites. In more translational projects we took up these phosho-regulations and identified their involvement in pathology relevant context (Altmuller et al., 2017; Lazarevic et al., 2017; Lazarevic et al., 2018).