The idea of guidance toward a target is central to the development of synapse-specific brain wiring. We now show how several thousand presynaptic growth cones self-pattern without target-dependent guidance during neural superposition wiring in Drosophila. Ablation of all postsynaptic lamina neurons or loss of target adhesion prevents the stabilization, but not the development of the pattern. Intravital imaging at the spatiotemporal resolution of growth cone dynamics in intact pupae and data-driven dynamics simulations reveal a mechanism by which >30,000 filopodia do not explore potential targets, but instead simultaneously generate and navigate a dynamic filopodial meshwork that steers growth directions. Hence, a guidance mechanism can emerge from the interactions of the growth cones being guided, suggesting self-organization as a mechanism leading to synaptic specificity in brain wiring.

While NMDA receptors are well known to be important for plasticity and synapse refinement, the role that they play in hippocampal synapse formation is controversial. Using organotypic slices, we identify an early developmental window when they play a role for driving synapse formation on to CA1 pyramidal neurons (PNs), in contrast to an absence of effects postnatally. By targeting an early window for abolition of NMDAR function in individual CA1 PNs in vivo, we find that these effects are synapse specific, and further that dendritic morphology is also affected. Using in vivo structural and functional imaging, we link dendritic NMDA-dependent calcium events to dynamic structural changes, providing an insight into how these effects may come about.

Mutations in genes encoding chromatin regulators are among the most frequent causes of autism spectrum disorders (ASD). Recognizing the critical role these genes play in adjusting the genome in reaction to environmental and cellular signals, we investigated how alterations in these ASD-related epigenetic regulators affect various types of synaptic changes in the brain networks of mice and humans. By integrating single-cell RNA sequencing techniques with behavioral and electrophysiological studies in mouse and human models, we uncovered the role of this class of genes in Hebbian and homeostatic plasticity.