Neuronal Interaction Dynamics During Neural Circuit Assembly - A live imaging and computational modeling approach for the Drosophila brain

• Applicants: Professor Dr. Peter Robin Hiesinger; Privatdozent Max Von Kleist, Ph.D.
• Subject Area: Developmental Neurobiology ; Experimental and Theoretical Network Neuroscience
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450430223

How does a neuron decide when and where to make a synapse? Synapse formation requires the interaction of axonal and dendritic projections of two neurons at the same time and place. Axonal and dendritic projections are highly dynamic structures, yet little is known about the role of their dynamic filopodial interactions during synapse-specific neural circuit assembly. To address this gap in knowledge, we combine live imaging of neural circuit assembly at the spatiotemporal resolution of synapse formation in the intact Drosophila brain with computational modeling; our goal is to understand the contribution of neuronal interaction dynamics to a neuron's developmental decision when and where to make a synapse. We are focusing on the developmentally dynamic decisions made by Drosophila R7 photoreceptor neurons and their (correct and incorrect) synaptic partners. Our collaboration between Drosophila neurobiologists and mathematicians originally formed to meet the challenge posed by 4D-tracking data of seemingly random dynamics of R7 axon terminals during the time period of synapse formation. The role of such filopodial dynamics during synapse formation has largely remained unknown. We therefore developed an interdisciplinary approach to quantitatively understand how individual axon terminals and their filopodia decide to initiate or stabilize synaptic contacts. We have performed two collaborative preliminary studies that form the basis for this grant proposal. These two projects were designed to understand the 'when' and the 'where' of R7's synapse formation choices. In our first study, we described and modelled a filopodial 'winner-takes-all' mechanism that ensures the formation of an appropriate number of synapses in time. In our second study, we described and modelled how filopodial kinetics not only affect synapse numbers, but also restrict inappropriate partner choice through a process of kinetic exclusion that critically contributes to wiring specificity. Both studies reported exclusively on the presynaptic R7 axon terminal, while the contribution of the post-synaptic partners has remained unknown. To our knowledge, no interaction dynamics have been reported for any pair of pre- and postsynaptic processes throughout an entire synapse formation process in a developing brain. Our goal is to provide a comprehensive description and computational model of the interaction dynamics during synapse formation including both partners (aim 1). Modulation of filopodial dynamics alters both synapse numbers and partners. Our approach is therefore designed to yield a model that quantitatively describes synapse formation choices that underlie circuit wiring, function and behavior (aim 2). When these studies are concluded, we will have established a model for the role of interaction dynamics during the assembly of a functionally relevant neural circuit in a developing brain.

• DFG Programme: Research Grants