Experience-dependent serotonergic signaling in glia regulates targeted synapse elimination.

The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.