Investigating the endolysosomal pathway and mechanical modulation at presynapses for enhanced understanding of neuronal function and dysfunction. Dr Daniela Ivanova Research Fellow Hugh Robson Building 15 George Square Edinburgh EH8 9XD Contact details Work: +44 (0) 131 651 1506 Email: D.Ivanova@ed.ac.uk Personal profile 2023 - present: Research Fellow, University of Edinburgh, UK 2017 - 2023: Postdoctoral Fellow, University of Edinburgh, UK 2015 - 2017: Postdoctoral Fellow, Leibniz Institute for Neurobiology, Magdeburg, Germany 2015: PhD (Molecular Neuroscience, Summa cum laude) Otto-von-Guericke University, Magdeburg, Germany Research Research stream 1) Endolysosomal Pathway and Synaptic Vesicle Recycling: A Unified Model for Presynaptic Function Synapses display a wide range of signalling strengths, largely due to variations in the molecular makeup of individual synaptic vesicles (SV). However, the root cause of this diversity remains an unresolved question. Beyond the immediate need for adjustments in SV composition, synapses must also continuously renew their proteome to avoid the buildup of harmful molecules. We propose a new model which posits that the endolysosomal pathway is at the core of presynaptic function. It enables adjustments in synaptic efficacy through sorting, retrieval, and degradation of SV components, thus facilitating continuous rejuvenation of the SV proteome. My overarching aim in this research stream is to establish a coherent framework for investigating membrane trafficking at the presynapse as an extension of the neuron’s widespread endolysosomal membrane trafficking network. This systematic model will integrate the control of neurotransmitter release with the long-term maintenance of synaptic integrity and function. Research stream 2) Mechanisms of Membrane Tension Modulation at the Presynaptic Plasma Membrane: Implications for Synaptic Function and Epileptogenesis The mechanical state of the plasma membrane modulates the structural and biochemical properties of synapses, influencing the kinetics of SV fusion and recycling. I investigate how mechanical cues at the presynapse control membrane dynamics and the precision of SV exo- and endocytosis. This understanding holds profound implications for shaping both synaptic transmission and plasticity, and is particularly relevant in the context of epilepsy, where mechanical factors significantly impact neuronal excitability and network dysfunction. Funding Epilepsy Research UK Supervision Akanksha Jain - PhD student co-supervised with Prof. Mike Cousin Relevant Publications Ivanova, D*. and Cousin, M.A*., 2022. Synaptic vesicle recycling and the endolysosomal system: a reappraisal of form and function. Frontiers in synaptic neuroscience, 14. Ivanova, D*., Dobson, K.L., Gajbhiye, A., Davenport, E.C., Hacker, D., Ultanir, S.K., Trost, M. and Cousin, M.A*., 2021. Control of synaptic vesicle release probability via VAMP4 targeting to endolysosomes. Science Advances, 7(18), p.eabf3873. Ivanova, D., Imig, C., Camacho, M., Reinhold, A., Guhathakurta, D., Montenegro-Venegas, C., Cousin, M.A., Gundelfinger, E.D., Rosenmund, C., Cooper, B. and Fejtova, A., 2020. CtBP1-mediated membrane fission contributes to effective recycling of synaptic vesicles. Cell reports, 30(7), pp.2444-2459. Ivanova, D., Dirks, A., Montenegro‐Venegas, C., Schöne, C., Altrock, W.D., Marini, C., Frischknecht, R., Schanze, D., Zenker, M., Gundelfinger, E.D. and Fejtova, A., 2015. Synaptic activity controls localization and function of Ct BP1 via binding to B assoon and P iccolo. The EMBO journal, 34(8), pp.1056-1077. Kontaxi, C., Ivanova, D., Davenport, E.C., Kind, P.C. and Cousin, M.A., 2023. Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals. Journal of Neuroscience, 10.1523/JNEUROSCI.1537-22.2023 *Corresponding author This article was published on 2022-10-17
