title: SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons.
abstract: Abnormal pain sensitivity is commonly associated with autism spectrum disorders (ASDs) and affects the life quality of ASD individuals. SHANK3 deficiency was implicated in ASD and pain dysregulation. Here, we report functional expression of SHANK3 in mouse dorsal root ganglion (DRG) sensory neurons and spinal cord presynaptic terminals. Homozygous and heterozygous Shank3 complete knockout (Δe4-22) results in impaired heat hyperalgesia in inflammatory and neuropathic pain. Specific deletion of Shank3 in Nav1.8-expressing sensory neurons also impairs heat hyperalgesia in homozygous and heterozygous mice. SHANK3 interacts with transient receptor potential subtype V1 (TRPV1) via Proline-rich region and regulates TRPV1 surface expression. Furthermore, capsaicin-induced spontaneous pain, inward currents in DRG neurons, and synaptic currents in spinal cord neurons are all reduced after Shank3 haploinsufficiency. Finally, partial knockdown of SHANK3 expression in human DRG neurons abrogates TRPV1 function. Our findings reveal a peripheral mechanism of SHANK3, which may underlie pain deficits in SHANK3-related ASDs.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Qingjian
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Bey
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lay
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Wonseok
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: yong-hui.jiang@dm.duke.edu.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: ru-rong.ji@duke.edu.
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D002211:Capsaicin / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000378:metabolism*; D018689:Sensory System Agents / Q000633:toxicity; D013116:Spinal Cord / Q000166:cytology; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C568318:Scn10a protein, mouse; D018689:Sensory System Agents; C492356:Shank3 protein, mouse; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D002211:Capsaicin
keywords: ASD; DRG; SHANK3; TRPV1; autism spectrum disorders; capsaicin; dorsal root ganglion; heat hyperalgesia; human sensory neurons; mice; primary sensory neurons; spinal cord dorsal horn