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. How does the genome encode brain wiring in light of this apparent contradiction? Synaptic specificity is the outcome of a long series of developmental processes and mechanisms before, during and after synapse formation. How much promiscuity is permissible or necessary at the moment of synaptic partner choice depends on the extent to which prior development restricts available partners or subsequent development corrects initially made synapses. Synaptic promiscuity at the moment of choice can thereby play important roles in the development of precise connectivity, but also facilitate developmental flexibility and robustness. In this review, we assess the experimental evidence for the prevalence and roles of promiscuous synapse formation during brain development. Many well-established experimental approaches are based on developmental genetic perturbation and an assessment of synaptic connectivity only in the adult; this can make it difficult to pinpoint when a given defect or mechanism occurred. In many cases, such studies reveal mechanisms that restrict partner availability already prior to synapse formation. Subsequently, at the moment of choice, factors including synaptic competency, interaction dynamics and molecular recognition further restrict synaptic partners. The discussion of the development of synaptic specificity through the lens of synaptic promiscuity suggests an algorithmic process based on neurons capable of promiscuous synapse formation that are continuously prevented from making the wrong choices, with no single mechanism or developmental time point sufficient to explain the outcome.
