Astrocyte response to motor neuron injury promotes structural synaptic plasticity via ​STAT3-regulated ​TSP-1 expression

The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach to compare the direct influence of normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations of AC–neuron signalling by reducing confounding effects imposed by inflammatory cells. We show direct evidence that perineuronal reactive ACs play a major role in maintaining neuronal circuitry following distant axotomy. We reveal a novel function of astrocytic ​signal transducer and activator of transcription-3 (​STAT3). ​STAT3 regulates perineuronal astrocytic process formation and re-expression of a synaptogenic molecule, ​thrombospondin-1 (​TSP-1), apart from supporting neuronal integrity. We demonstrate that, through this new pathway, ​TSP-1 is responsible for the remote AC-mediated recovery of excitatory synapses onto axotomized motor neurons in adult mice. These data provide new targets for neuroprotective therapies via optimizing AC-driven plasticity.