Cortical astrocytes rewire somatosensory cortical circuits for peripheral neuropathic pain

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

Research output: Contribution to journalArticlepeer-review

140 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1983-1997
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number5
DOIs
Publication statusPublished - 2 May 2016

Bibliographical note

Funding Information:
We thank M. Kano for the gift of Elvax beads; D.X. Li, H. Yoon, S.H. Kim, K. Nakamura, T. Toda, R. Akiyoshi, A. Miyamoto, K. Eto, H. Wake, and H. Ishibashi for excellent technical assistance and critical discussions on the experiments. This work was supported by a Core Research for Evolutional Science and Technology (CREST) grant from the Japan Agency for Medical Research and Development (AMED) and from the Japan Science and Technology Agency (JST) (to J. Nabekura); Grant-in-Aids for Scientific Research (A) (22240042, to J. Nabekura) and (S) (25221002, to K. Mikoshiba) from the Japan Society for the Promotion of Science (JSPS); a Grant-in-Aid for Scientific Research on an Innovative Area from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to S. Koizumi); and by grants from the National Research Foundation of Korea funded by the Korean government (NRF-2013R1A1A1012403 and MEST-2012-0005755, to S.K. Kim and MSIP-2011-0030737, to S.J. Kim). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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