Motor learning and dopamine-dependent striatal synaptic plasticity are controlled by astrocytic MEGF10

Abstract

Dopamine regulates striatal activity during motor learning by facilitating synaptic plasticity of dopamine receptor-expressing medium spiny neurons (MSNs). Despite recent advances in our understanding of how dopamine controls synapse plasticity, its role in synapse remodeling, especially in relation with glial cells, remains largely unexplored. Here, we demonstrate that astrocytic phagocytosis receptor MEGF10, but not MERTK, is required for the engulfment of corticostriatal excitatory synapses on MSNs during motor skill acquisition. Deletion of astrocytic Megf10 exhibited impaired long-term potentiation and depression (LTP and LTD) and attenuated motor learning-induced elevation of synaptic strength. Modulation of striatal activity by chemogenetic activation of either corticostriatal excitatory transmission or dopamine release from substantia nigra pars compacta (SNc) significantly enhances astrocytic, but not other glial, elimination of striatal synapses. Importantly, we further discovered that the increase of dopamine levels in the striatum as well as motor learning differentially controls postsynaptic elimination of MSNs depending on their dopamine receptor subtypes, subsequently resulting in MEGF10- dependent changes in synapse remodeling and the quantal properties of corticostriatal synapses in MSNs. These findings establish that astrocytic MEGF10 is a pivotal mediator of synapse remodeling and plasticity in the striatum, controlled by neuronal activity and dopamine level.