Dynamic interplay between voltage-gated calcium channels and presynaptic cytomatrix

• Applicants: Professorin Dr. Anna Fejtová; Professor Dr. Martin Heine
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436933646

Synaptic neurotransmission plays a key role in the neuronal communication. The presynaptic efficacy, i.e. the likelihood, by which an incoming action potential induces a release of neurotransmitter, largely differs between individual synapses even within the same axonal segment and is subject of usage-dependent regulations. These changes in release efficacy contribute to the plasticity of the brain, which underlying adaptive behaviour and cognition. Within this proposal we would like to investigate molecular dynamics of presynaptic neurotransmitter release sites and its role in modulation of neurotransmission. Specifically, we focus here on mechanisms behind functional regulations of presynaptic voltage-gated calcium channels (VGCC), which are central for the control of presynaptic release and plasticity as they are the source of calcium for evoked neurotransmitter release as well as for presynaptic calcium-induced signalling. We propose that the dynamic recruitment of VGCC to release sites depend on multiple interactions with presynaptic scaffold proteins and that regulation of individual interaction within the VGCC complex can importantly tune mode of neurotransmission at individual synapses. We will focus on RIMs, RBP and Bsn/Pclo, which link VGCC or SV through multiple direct interactions and are essential for the structural and functional integrity of presynapse. In our synergistic approach, we will interfere with specific interaction within the VGCC-scaffold complex using genetics and synthetic compounds in cultured dissociated neurons and organotypic and acute hippocampal slices and apply super resolution-localization microscopy, in vivo imaging and electrophysiology to analyse contribution of individual VGCC-scaffold interaction on dynamic organisation, function and plasticity of release sites. In an integrated exploratory project part we will map neuronal activity-induced transcriptional reprogramming potentially contributing to functional shaping of release sites during homeostatic plasticity.

• DFG Programme: Research Grants