Synaptic promiscuity in brain development
Precise synaptic connectivity is a prerequisite for the function of neural circuits, yet individual neurons, taken out of their developmental context, readily form unspecific synapses. The goal of this proposal is to understand the roles and requirements of such promiscuous synapse formation during brain development. The observation of promiscuous synapse formation is not at odds with precise outcomes. The developmental program can ensure correct partnerships between neurons that form synapses promiscuously, but to what degree remains largely unresolved. My group has developed live imaging and optogenetic manipulations of dynamic synaptic choice processes in the intact developing fly brain. We found that time, location and the kinetics of filopodial interactions restrict to a remarkable degree the specificity of synaptic contacts between neurons that can form synapses with many partners if not actively prevented from doing so. A second surprise finding that motivates this proposal suggests markedly different connectomes of flies that developed at 18°C and 25°C, including synapse numbers and partnerships. These differences can be traced back to interaction kinetics during development, thus revealing a level of synaptic promiscuity that can be exposed through temperature alone. The time is ripe for a quantitative assessment of the extent to which synaptic connections are the result of developmentally regulated promiscuous synapse formation. The quest to understand the molecular mechanisms of brain wiring has largely focused on guidance cues and synaptic recognition, fields in which great progress continues to be made. This proposal offers to approach the question of synaptic specificity from the much rarer, but complementary perspective of the alternative limiting case, the hypothesis of synaptic promiscuity. SynPromiscuity is devised to balance the risks of a contrarian approach with its relevance for neurodevelopmental precision and plasticity in health and disease.