title: 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.forename: Sun Kwang
authors.initials: SK
authors.lastname: Kim
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Eiji
authors.initials: E
authors.lastname: Shigetomi
authors.forename: Youichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inada
authors.forename: Seung Eon
authors.initials: SE
authors.lastname: Roh
authors.forename: Sang Jeong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Gihyun
authors.initials: G
authors.lastname: Lee
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Bae
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Moorhouse
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Yugo
authors.initials: Y
authors.lastname: Fukazawa
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
authors.forename: Junichi
authors.initials: J
authors.lastname: Nabekura
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000378:metabolism; D009437:Neuralgia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D015398:Signal Transduction; D013003:Somatosensory Cortex / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism
chemical_list: C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse