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

We study molecular mechanisms behind rapid (in frame of seconds and minutes) changes in presynaptic function. They are mostly synapse-specific and mediated by posttranslational modification of synaptic proteins.

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.

Presynaptic CaV2.1 channels are confined in nanodomains, for which size and dwell time are modulated by network activity. Heck et al. show that changing the affinity to scaffold proteins by alternative splicing of CaV2.1 directly affects short-term plasticity.

Regulation of SV recycling

Deletion of the giant presynaptic scaffolding protein Bassoon leads to a reduction 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 with contribution of Carolina Montenegro-Venegas from Magdeburg we addressed the molecular basis of this phenotype using imaging of SV recycling in cultured neurons. 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). 

Presynapse-to-nucleus signalling

We investigate presynapse-to-nucleus signalling that drives neuronal activity-driven reconfiguration of gene expressional programs, which are required to make usage-dependent changes in presynaptic function persistent.

CtBP1 shuttles between presynapse and nucleus to control the expression of neuroplasticity-related genes dependently on neruonal activity and metabolic status. (Ivanova et al., 2015; Ivanova et al., 2016)