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Séminaire impromptu - Prof. Kim, Sun KwangIn vivo two-photon imaging study on astrocytes-mediated synaptic rewiring in the mouse S1 cortex during chronic pain

Abstract :


 Neuropathic pain following peripheral nerve injury is characterized by mechanical allodynia, a painful response to innocuous tactile stimulation.
Although this chronic pain has been known to be induced by glial activation and altered nociceptive transmission within the spinal cord, an effective treatment is still insufficient, suggesting that novel therapeutic targets are critically needed. One such target may be the remodeling of synaptic connections in the primary somatosensory (S1) cortex that is highly associated with the severity of neuropathic mechanical allodynia. However, the causal relationship of S1 synapse remodeling to mechanical allodynia and its underlying cellular/molecular mechanisms remain unknown. Furthermore, whether and how glial cells contribute to S1 synaptic plasticity is still unclear. Using in vivo two-photon microscopy imaging with genetic and pharmacological manipulations, here we show that partial sciatic nerve ligation (PSL) injury induces an early re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astrocytes, which elicits spontaneous somatic Ca2+ transients, thrombospondin-1 release and synapse formation. Such activation of S1 astrocytes was evident only during a critical period (~1w post-injury), correlating with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover following PSL injury. Blocking this astrocytic signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of injury induced long-lasting (>1 month) allodynia. Thus, these synaptogenic astrocytes are a key trigger for S1 synaptic rewiring that mediates neuropathic pain mechanical allodynia.

 

Selected publications

1. S.K. Kim and J. Nabekura, (2011) Journal of Neuroscience. 31, 5477-5482.

2. S.K. Kim et al., (2011) Molecular Pain. 7, 87.

3. S.K. Kim et al., (2016) Journal of Clinical Investigation. 126, 1983-1997