Dynamic interactions between presynaptic Ca2+ channels and neurexins

• Applicants: Professor Dr. Martin Heine; Professor Dr. Markus Missler
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 533473719

Synaptic contacts between neurons are tightly organized subcellular compartments that are function in a probabilistic manner. The probability of synaptic function gives the nervous system the flexibility to change the communication and information processing between neurons and to react to fast and/or long-lasting activity changes. The release of transmitter within the synaptic cleft between the pre- and postsynaptic membrane can only trigger a transmission of the signal if both the release site and the postsynaptic receptor population are well aligned to each other. Adhesion molecules are well known to be critical for such a precise alignment of few tens of nano meter within synapses. Using imaging techniques in combination with functional readouts has shown that the molecular composition of synaptic membranes is very dynamic during synaptic activity and allows fast adaptation to altered activity profiles. In the proposed project we will focus on the organization of the presynaptic adhesion molecule α-neurexin and his impact on the organization of voltage gated calcium channels via the extracellular α2δ auxiliary subunits. Since these molecules are members of large protein families, we will focus on a distinct combination of variants. We aim to investigate the interplay of CaV2.1, α2δ-3 and Nrxn1α because (I) Ca2+ influx through CaV2.1 is reduced in absence of α-Nrxns and Nrxn1α rescues this defect partially, (II) Nrxn1α and α2δ-3 were proposed to interact functionally, (III) CaV2.1, Nrxn1α and α2δ-3 have been individually shown to play a prominent role in Ca2+-dependent release from GABAergic boutons, which are not well investigated with respect to their nanoscale organization, (IV) Nrxn1α and α2δ-3 affect the density of developing inhibitory synapses, (V) all three molecules are prominently expressed in excitatory and inhibitory hippocampal neurons and (VI) Nrxn1α and α2δ-3 are risk factors for neurodevelopmental disorders due to an imbalance of excitatory/inhibitory activity within neuronal networks. We will monitor and manipulate the localization and dynamics of the CaV2.1/α2δ-3/Nrxn1α complex to determine how their putative crosstalk affects the function of individual synapses as well as effective synaptic connectivity in recurrent neuronal networks. The distinctive strategic hallmark of our work program is to investigate the behavior of endogenous CaV2.1, Nrxn1α and α2δ-3 molecules, to avoid shortcomings and potential artifacts of overexpression studies. We aim by the use of single molecule imaging techniques in combination with functional optical and electrical readouts to elucidate how these three molecules will interact on the cell surface and impact in the function of synapses in neuronal networks and the balance between excitatory and inhibitory synaptic transmission.

• DFG Programme: Research Grants