Self-organization of modular network architecture by activity-dependent neuronal migration and outgrowth

The spatial distribution of neurons and activity-dependent neurite outgrowth shape long-range interaction, recurrent local connectivity and the modularity in neuronal networks. We investigated how this mesoscale architecture develops by interaction of neurite outgrowth, cell migration and activity in cultured networks of rat cortical neurons and show that simple rules can explain variations of network modularity. In contrast to theoretical studies on activity-dependent outgrowth but consistent with predictions for modular networks, spontaneous activity and the rate of synchronized bursts increased with clustering, whereas peak firing rates in bursts increased in highly interconnected homogeneous networks. As Ca²⁺ influx increased exponentially with increasing network recruitment during bursts, its modulation was highly correlated to peak firing rates. During network maturation, long-term estimates of Ca²⁺ influx showed convergence, even for highly different mesoscale architectures, neurite extent, connectivity, modularity and average activity levels, indicating homeostatic regulation towards a common set-point of Ca²⁺ influx.