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Neuron-glia interactions play a critical role in the regulation of synapse formation and neuron specification. The cellular and molecular mechanisms by which neurons and astrocytes communicate and coordinate are not well understood. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity and functional circuit development. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-specific astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses, conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, we determined that Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

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 the 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 nearby 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.