Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism

Sensory experience remodels neural circuits in the early postnatal brain through mechanisms that remain to be elucidated. Applying a new method of ultrastructural analysis to the retinogeniculate circuit, we find that visual experience alters the number and structure of synapses between the retina and the thalamus. These changes require vision-dependent transcription of the receptor Fn14 in thalamic relay neurons and the induction of its ligand TWEAK in microglia. Fn14 functions to increase the number of bulbous spine-associated synapses at retinogeniculate connections, likely contributing to the strengthening of the circuit that occurs in response to visual experience. However, at retinogeniculate connections near TWEAK-expressing microglia, TWEAK signals via Fn14 to restrict the number of bulbous spines on relay neurons, leading to the elimination of a subset of connections. Thus, TWEAK and Fn14 represent an intercellular signaling axis through which microglia shape retinogeniculate connectivity in response to sensory experience. [Display omitted] •Experience induces Fn14 expression in neurons and TWEAK expression in microglia•Fn14 increases the number of spine-associated synapses when not bound by TWEAK•Microglial TWEAK signals through neuronal Fn14 to locally decrease synapse numbers•Microglia-driven synapse loss occurs through a non-phagocytic mechanism Sensory experience induces Fn14 expression in relay neurons and TWEAK expression in microglia to drive refinement of retinogeniculate connectivity. Microglial TWEAK signals through neuronal Fn14 to eliminate a subset of synapses proximal to TWEAK-expressing microglia, whereas Fn14 acts alone at other synapses to strengthen connectivity.