Dopamine-dependent glial synapse engulfment in the striatum

Abstract

Glial cells play crucial roles in maintaining neural circuitry through synaptic pruning under both physiological and pathological conditions. However, their specific contributions to synapse engulfment in the striatum remains poorly understood. Using a combination of high-resolution confocal imaging, electrophysiology, chemogenetics, optogenetics, and immunohistochemistry, we demonstrate that the astrocytic phagocytosis receptor MEGF10, but not MERTK, is required for the engulfment of corticostriatal excitatory synapses on MSNs during motor skill acquisition. Astrocyte-specific deletion of Megf10 impairs long-term potentiation (LTP) and attenuates motor learning-induced elevation of synaptic strength. Notably, modulation of striatal activity via chemogenetic activation of midbrain dopamine neurons significantly enhances astrocytic, but not microglial, elimination of corticostriatal synapses. In the second part of the talk, we present evidence indicating that dopaminergic presynaptic boutons in the striatum are primarily engulfed by microglia rather than astrocytes. Furthermore, this microglia-mediated engulfment of dopaminergic boutons is dynamically regulated by the activation state of dopamine neurons and significantly influences the functional properties of dopamine synapses in the striatum. Collectively, these findings reveal previously unrecognized mechanisms by which glial cells dynamically shape striatal circuitry and function through dopaminergic modulation.