Abstract
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.
Highlights
The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood
We provide the underlying mechanism, showing that signal transducer and activator of transcription-3 (STAT3) activation upregulates astrocytic TSP-1 re-expression and release, which is required to facilitate the recovery of synaptic input onto surviving motor neurons after their distant axonal insult
To explore whether STAT3 signalling plays a key role in the AC response to remote axonal injury, we used glial fibrillary acidic protein (GFAP)-Cre/STAT3-loxP conditional knockout (CKO)
Summary
The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Recent studies using experimental ischaemic CNS damage reported that thrombospondin-1/2 can be re-expressed locally at the lesion site[15,16], but their regulation in reactive ACs remains unresolved The complexity of these lesions may cloud direct interpretations of default AC behaviour, and the above findings may not be relevant to situations when ACs are remotely activated in a less inflammatory environment[17,18,19]. We provide the underlying mechanism, showing that STAT3 activation upregulates astrocytic TSP-1 re-expression and release, which is required to facilitate the recovery of synaptic input onto surviving motor neurons after their distant axonal insult
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