Organizational principles governing synapse types in a whole-brain connectome

Neurons are classically viewed as polarized elements in which dendrites receive synaptic input and axons provide output. However, many neurons contain intermingled presynaptic and postsynaptic sites, enabling non-canonical forms of connectivity beyond axo-dendritic interactions. How such mixed polarity shapes connectivity across an entire nervous system remains unknown. Here, using the complete Drosophila connectome of an adult brain (approximately 140,000 neurons and >80 million synapses), we systematically mapped synapse types across neuronal compartments, cell types, and brain regions. We found that mixed polarity is widespread yet highly structured across neuronal populations. Approximately one third of synapses between polarized neurons are non-canonical, including axo-axonic, dendrodendritic, and dendro-axonic interactions. Remarkably, synapse type can be predicted from a simple axis of neuronal complexity derived from morphology and connectivity. Low-complexity neurons, which dominate early visual circuits, preferentially interact through dendrites, whereas larger and more highly connected neurons enriched in central brain regions preferentially interact through axons. Mixed polarity also strongly promotes reciprocal connectivity, which is dominated by non-canonical motifs. Finally, we identified postsynaptic terminals on presynaptic boutons as a widespread anatomical motif associated with local reciprocal and non-canonical interactions. Together, these findings reveal organizational principles linking neuronal architecture, synapse type, and circuit connectivity across a complete brain.