Activity-dependent Sonic hedgehog signaling promotes astrocyte modulation of synaptic plasticity

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Activity regulates gene expression in astrocytes, yet the molecular mechanisms by which such activity is translated into functional changes in gene expression have remained largely unknown. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that sensory experience stimulates SHH signaling in cortical astrocytes. Whisker stimulation and chemogenetic activation both increase SHH activity in deep layers of the somatosensory cortex, where neuron-astrocyte SHH signaling is predominantly found. Selective loss of SHH signaling in astrocytes occludes experience-dependent structural plasticity of synapses. We further demonstrate that sensory experience promotes expression of the synapse modifying molecules, Hevin and SPARC, in a SHH-dependent manner. Taken together, these data identify SHH signaling as an activity-dependent, neuronal derived cue that stimulates astrocyte interactions with synapses and promotes synaptic plasticity.