Glial Serotonergic Signaling as a Gatekeeper in Brain Circuit Remodeling

Abstract

This dissertation investigates how glial serotonergic signaling regulates experience-dependent neural circuit remodeling during critical periods and how these mechanisms may be harnessed to re-open plasticity in adulthood. Using the Drosophila olfactory system as a genetically tractable model, this work identifies a previously unrecognized glia-to-glia serotonergic signaling pathway that directs targeted synapse elimination during early-life critical period refinement. Specifically, this dissertation demonstrates that glial serotonin biosynthesis via tryptophan hydroxylase and glial 5-HT2A receptor signaling are both essential for sensory experience-dependent synaptic pruning. Distinct glial subtypes were found to perform specialized roles, with ensheathing glia providing serotonin signaling and astrocyte-like glia mediating downstream 5-HT2A receptor-dependent responses required for circuit remodeling. Mechanistically, serotonergic signaling was shown to regulate matrix metalloproteinase-dependent extracellular matrix remodeling, enabling glial infiltration and phagocytic synapse elimination. Importantly, conditional activation of glial 5-HT2A receptor signaling in mature adults was sufficient to re-establish “critical period-like” plasticity beyond normal developmental closure. Together, these findings reveal glia as central effectors of serotonergic control over neural circuit refinement and identify glial serotonergic signaling as a potential therapeutic target for restoring plasticity in neurodevelopmental and neuropsychiatric disorders associated with impaired synaptic remodeling.