It is well-established that synapse formation involves highly selective chemospecific mechanisms, but how neuron arbors are positioned before synapse formation remains unclear. Using 3D reconstructions of 298 neocortical cells of different types (including nest basket, small basket, large basket, bitufted, pyramidal, and Martinotti cells), we constructed a structural model of a cortical microcircuit, in which cells of different types were independently and randomly placed. We compared the positions of physical appositions resulting from the incidental overlap of axonal and dendritic arbors in the model (statistical structural connectivity) with the positions of putative functional synapses (functional synaptic connectivity) in 90 synaptic connections reconstructed from cortical slice preparations. Overall, we found that statistical connectivity predicted an average of 74 ± 2.7% (mean ± SEM) synapse location distributions for nine types of cortical connections. This finding suggests that chemospecific attractive and repulsive mechanisms generally do not result in pairwise-specific connectivity. In some cases, however, the predicted distributions do not match precisely, indicating that chemospecific steering and aligning of the arbors may occur for some types of connections. This finding suggests that random alignment of axonal and dendritic arbors provides a sufficient foundation for specific functional connectivity to emerge in local neural microcircuits.connectome | microcircuitry | neocortex | neuronal connectivity D uring development, a broad range of molecular signaling mechanisms act to form the neocortical layers (1, 2), lay down guidance tracts for neurons to position themselves and grow their axonal and dendritic arbors (3, 4), shape the morphologies of different types of neurons (5), guide input axons to specific layers (6), trigger differentiation and clustered arborizations of axonal arbors (7), prune axonal arbors in an activitydependent manner (8), guide axonal growth along the axon initial segment (9), and selectively form synapses between specific types of neurons (10-12). Molecular mechanisms also contribute to the activity-triggered formation of synapses between specific pairs of neurons (13). The mechanisms determining this selective connectivity have been a subject of active debate for over a century (3,(14)(15)(16)(17), with proposals ranging from the idea of "chemical relations" between connected neurons in the work by Langley (18) to the "chemoaffinity hypothesis" (the idea that precise synaptic positioning is specified by "highly specific cytochemical affinities" between neurons) in the work by Sperry (19). The result is an intriguing map of synaptic connections between all neurons and specific types of neurons, commonly called the connectome. How the connectome arises is still debated (20). A question that is at the core of the debate is to what extent do chemospecific mechanisms specifically align neuronal arbors between neurons before synaptic connections are formed.Spines are dynamic s...