Research

The lab is interested in molecular and cellular mechanisms that control plasticity of neurotransmitter release and their role in normal brain function and in disease.

Our publications on PubMed.

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, we addressed the molecular basis of this phenotype using imaging of SV recycling in cultured neurons (Montenegro-Venegas et al., 2022). We identified dysregulation of multiple synaptic kinases and phosphatases in absence of bassoon, which leads to the changes 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 in the context of Alzheimer’s disease and neuropsychiatric conditions (Altmuller et al., 2017; Lazarevic et al., 2017; Lazarevic et al., 2018; Anni et al., 2021; Guhathakurta et al., in preparation). 

Anni et al., (2021) demonstrated that Aβ1-42 and Aβ1-16, but not Aβ17-42, increased size of the recycling pool of synaptic vesicles (SV). This presynaptic effect was driven by enhancement of endogenous cholinergic signalling via α7 nicotinic acetylcholine receptors, which led to activation of calcineurin, dephosphorylation of synapsin 1 and consequently resulted in reorganization of functional pools of SV increasing their availability for sustained neurotransmission. These results identify synapsin 1 as a molecular target of Aβ and reveal an effect of physiological concentrations of Aβ on cholinergic modulation of glutamatergic neurotransmission.

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. (2019) show that changing the affinity to scaffold proteins by alternative splicing of CaV2.1 directly affects short-term plasticity.

Dual role of CtBP1 in neurons

Presynapses develop often far away from the neuronal cell bodies. Therefore, specific mechanisms are required for communicating signals from presynaptic compartment back towards the nucleus. In this context, we study the neuronal functions of multifunctional scaffold CtBP1. We have reported its dual localization to the presynaptic active zones and to the nucleus and shuttling between these two locations in dependence of neuronal activity and cellular metabolic status (tom Dieck et al., 2005; Hubler et al., 2012). This shuttling has effect on expression of neurodevelopmental and neuroplasticity genes (Ivanova et al., 2015; Ivanova et al., 2016; Ivanova et al., 2020). In our current work, we aim to understand, what the signals are that control the shuttling of CtBP1 and how this process contributes to the remodelling gene expression patterns during neurodevelopment and neuroplasticity.

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)

Neurotransmitter release relies on a complex sequence of membrane trafficking events, which is tightly controlled in space and time by dynamic interactions of multiple proteins and lipids. Recently, we described a new function of CtBP1 at presynapse: It contributes to the retrieval of SV by recruitment and activation of lipid-modifying enzymes (Ivanova et al., 2020).

Ivanova et al. (2020) demonstrate a dual role of CtBP1 in synaptic transmission. While nuclear CtBP1 restricts synaptogenesis and vesicular release probability, presynaptic CtBP1 promotes compensatory endocytosis via activation of the lipid enzyme PLD1. Phosphorylation by Pak1 controls the redistribution of CtBP1 from active zones towards endocytic sites linking presynaptic exo- and endocytosis.

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