A Developmental Algorithm for Synapse-Specific Wiring of the Drosophila Visual Map

During brain development, genetic information and environmental input drive neural circuit assembly that requires matching of correct pre- and post-synaptic partners. In cases when environmental input has no instructive role in synaptic partner selection, genetic information alone must suffice to specify synapses in neural circuits. However, how a limited amount of genetic information is translated into developmental algorithms for synapse specification is unclear. A major thrust of the field has been the quest to identify guidance cues and molecular matchmaking codes underlying brain wiring. In this work, I present a complementary approach, in which the characterization of the developmental algorithm based on simple rules is the primary focus, and the molecules executing these rules secondary. I propose that simple rules underlying developmental algorithms can be sufficient to establish seemingly complex wiring diagrams without an elaborate matchmaking code between synaptic partners. I used Drosophila visual map, which is a genetically encoded neural circuit, as a model system to test my hypothesis. During visual map formation, around 4800 photoreceptors simultaneously project to their correct target layer 'lamina' in the brain to find their correct synaptic partners. I developed a 2-photon microscopy-based, intravital imaging technique with which I could observe the development of individual photoreceptor growth cones at the spatiotemporal resolution of filopodial dynamics over 24 hours during visual map formation. Based on these imaging data, I spearheaded a group effort to formulate and computationally test simple rules that are sufficient for photoreceptors to sort to their correct partners without a requirement for precise matchmaking codes. A key prediction of the model was that the post-synaptic partners may not act as target cues for the pre-synaptic photoreceptors. In the second part of my thesis, I tested this hypothesis by ablating and blocking membrane dynamics of post-synaptic partners. My findings indicate that indeed post-synaptic partners of photoreceptors do not act as target cues for photoreceptors, but are necessary during a preceding step in the developmental algorithm to ensure correct wiring. In brief, results I presented in this work support the idea that correct synaptic partner selection can be achieved through a developmental algorithm based on simple rules that sorts correct cells together prior to synapse formation.