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

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.

Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain

“…Astrocytes respond to sensory inputs or synaptic activity with intracellular Ca 2+ rises and remodeling of perisynaptic astrocytic processes, resulting in the release of neuroactive substances that may not only acutely affect synaptic and neuronal activity, but may also result in slower and more chronic aspects of neuronal plasticity (23,(51)(52)(53)(54)(55). Indeed, slower astrocyte-neuron interaction is more consistent with the temporal dynamics of astrocytic Ca 2+ waves, which are much slower than the rapid time course of synaptic transmission (53).…”

“…Astrocytes secrete a number of molecules that are not defined as gliotransmitters but that nevertheless directly modulate synaptic structures and thereby synaptic function (23) on a slower time scale. We focused on one class of these, the TSPs, because (a) they bind to synaptic α 2 δ-1 receptors to induce excitatory synaptogenesis in vitro and in vivo; (b) gabapentin, which inhibits this synaptogenic action by antagonizing TSP binding to α 2 δ-1, is effective against neuropathic pain (32); (c) dendritic spine malformations and reduced synaptic density in Down syndrome brain are directly linked to deficits in astrocytic TSP-1 protein expressions (56); and (d) astrocytes near the injured neuronal cell bodies release TSPs to cause functional and structural synaptic plasticity in vitro and in vivo (50,55). We found that TSP-1 release from S1 astrocytes is markedly increased 1 9 9 3 jci.org…”

Cell biology of spinal cord injury and repair

“…Hypertrophic astrocytes closely intermingle with viable neurons in spared but reactive tissue (refs. 5, 13, 123; Figure 1, A and B; and Figure 3A), where they may influence axon sprouting and synapse plasticity by modulating expression of perineuronal net-associated proteins such as neurocan and tenascin-C (124,125) or by producing thrombospondin (126).…”

“…Enzymatic digestion of perineuronal net molecules or blockade of their neuronal receptors can augment task-specific rehabilitation after incomplete SCI (99,102,108). Perineuronal reactive astrocytes promote re-formation of excitatory synaptic inputs after injury via a thrombospondin-and STAT3-dependent mechanism (126). Sprouting of descending supraspinal axons to form new relay connections after incomplete SCI can be augmented by local delivery of growth factors (141), by chronic electrical stimulation (142), or by the increasing of intrinsic neuron growth capacity by deletion of PTEN and SOCS3 (143).…”

Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury

“…Specialized membranes, such as at synapses, are susceptible to unique environmental changes within the injured brain, where astrocytes in the tripartite synapse contribute to synaptic transmission and function (1)(2)(3). TBI is known to result in astrocyte reactivity, which has both beneficial and deleterious effects on injury progression and recovery; however, few studies have examined the effects of astrogliosis on synaptic stability in the CNS (4)(5)(6).…”