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Unraveling cellular and molecular mechanisms that coordinate pre- and postsynaptic maturation by intravital imaging in the Drosophila central nervous system

Subject Area Molecular Biology and Physiology of Neurons and Glial Cells
Developmental Biology
Term from 2016 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 316044542
 
Final Report Year 2024

Final Report Abstract

Animals need to maintain neuronal circuit function while adapting to a body growing in size or changing environmental conditions. Mechanisms that regulate the initial assembly of neuronal circuits have been studied intensively. However, much less is known about how growth is regulated during post-embryonic phases, following the integration of neurons into functional circuits. In the first part of this project, we shown that trans-synaptic Jeb-Alk signaling acts to slow motor circuit growth upon synapse formation in Drosophila larvae, and as a result, maintains functional stability during postembryonic growth. Jeb is released from cholinergic terminals and activates postsynaptic Alk, which negatively regulates the proliferation of post-, but not pre-, synaptic specializations. Alk activation by Jeb also seems to elicit an as yet uncharacterized retrograde signal that inhibits the formation of presynaptic filopodia. We find that dendritic structural plasticity is promoted by presynaptic filopodia, but repressed by increasing numbers of postsynaptic specializations. Based on our observations, we propose a model that presynaptic filopodia enhance dendritic growth. Once a dendritic protrusion contacts a presynaptic release site, presynaptic Jeb induces dendritic Alk activation. This Alk activation then acts to inhibit addition or differentiation of further postsynaptic specializations nearby. It also elicits retrograde signaling that dampens presynaptic filopodial dynamics, thus curbing presynaptic exploratory contacts in the immediate vicinity. Our data point to Alk-receptor activation being interpreted locally at a forming synaptic contact, therefore repressing nearby formation of other contacts and thus reducing the density of postsynaptic specializations along a dendritic arbor. In the 2nd part of this project, we investigated the mechanisms driving synaptic plasticity during postembryonic growth and maintenance at the level of individual proteins, using the presynaptically localizing protein Bruchpilot (brp) and RIM binding protein (rbp) as a model. Previous work demonstrated that synaptic coupling strength positively correlates with both Brp and rbp amounts at individual synaptic release sites. Synaptic strengthening may arise by accumulation of these proteins as a function of synapse age. Alternatively, protein integration and removal may be regulated at individual release sites, independent of age. To distinguish these hypotheses, we conducted pulse-chase type of experiments in which newly synthesized Brp and rbp proteins were differentially labeled from pre-existing such proteins. We find that there is no correlation between overall amounts of brp / rbp , and the rate of inclusion of newly synthesized protein. This demonstrates that accumulation of neither brp nor rbp is a mere function of synaptic age, but likely depends on mechanism that target synaptic strengthening to select presynaptic release sites. This part of the work is currently submitted for publication as part of a collaborative project with the Sigrist lab at Freie Universität Berlin.

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