Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain
Sun Kwang Kim, … , Schuichi Koizumi, Junichi Nabekura
Sun Kwang Kim, … , Schuichi Koizumi, Junichi Nabekura
Published April 11, 2016
Citation Information: J Clin Invest. 2016;126(5):1983-1997. https://doi.org/10.1172/JCI82859.
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Research Article

Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain

Abstract

Long-term treatments to ameliorate peripheral neuropathic pain that includes mechanical allodynia are limited. While glial activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse formation. This S1 astrocyte reactivation was evident only during the first week after injury and correlated with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover. Blocking the astrocytic mGluR5-signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of any peripheral injury induced long-lasting (>1 month) allodynia. We conclude that reawakened astrocytes are a key trigger for S1 circuit rewiring and that this contributes to neuropathic mechanical allodynia.

Authors

Sun Kwang Kim, Hideaki Hayashi, Tatsuya Ishikawa, Keisuke Shibata, Eiji Shigetomi, Youichi Shinozaki, Hiroyuki Inada, Seung Eon Roh, Sang Jeong Kim, Gihyun Lee, Hyunsu Bae, Andrew J. Moorhouse, Katsuhiko Mikoshiba, Yugo Fukazawa, Schuichi Koizumi, Junichi Nabekura

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Figure 5

TSP-1 released from S1 astrocytes following PSL injury promotes synaptic rewiring and sustained mechanical allodynia.

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TSP-1 released from S1 astrocytes following PSL injury promotes synaptic...
(A) Images of the same S1 apical dendrite before and 3 days after PSL injury with sustained (Elvax) saline or gabapentin application. Arrowheads indicate spine formation (red) and elimination (blue). Scale bar: 2 μm. Graphs: Spine formation (top) and elimination (bottom) rates in saline-administered, sham-operated mice (n = 24 dendrites/3 mice), PSL-injured mice (n = 17 dendrites/3 mice), and gabapentin-infused, PSL-injured mice (n = 21 dendrites/3 mice). **P < 0.01 and ***P < 0.001, by 1-way ANOVA. (B) Mean mechanical thresholds following PSL injury in control (n = 7), gabapentin-infused (n = 5), and TSP-1 siRNA–injected (n = 6) mice. *P < 0.05, **P < 0.01, and ***P < 0.001 versus control, by 1-way ANOVA. (C) Western blots demonstrate selective knockdown of TSP-1 expression in S1 cortex following TSP-1 siRNA injection. As for positive control of TSP-1, recombinant human TSP-1 (hTSP-1) was loaded (left band). Graphs: Quantitative analysis of Western blots (n = 4). **P < 0.01, by unpaired t test. Spine formation (left) and elimination (right) rates in control siRNA-injected mice (siControl, n = 11 dendrites/3 mice) and TSP-1 siRNA–injected mice (siTSP-1, n = 8 dendrites/2 mice). **P < 0.01, by unpaired t test. (D) Single injection of TSP-1 protein (n = 6 mice), but not PBS (n = 6), into S1 cortex induced mechanical hypersensitivity that lasted at least 4 weeks. **P < 0.01 and ***P < 0.001, by unpaired t test. Images of the same S1 apical dendrite in naive mice before and 1 day after an injection of PBS (upper panels) or TSP-1 (lower panels). Arrowheads indicate spine formation. Scale bar: 2 μm. Inset graph: Spine formation rates in PBS-injected (n = 8 dendrites/3 mice) and TSP-1–injected (n = 9 dendrites/3 mice) mice. **P < 0.01, by unpaired t test. Error bars represent the mean ± SEM.