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Neuron. 2016 Dec 21;92(6):1279-1293. doi: 10.1016/j.neuron.2016.11.007. Epub 2016 Dec 1.

SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons.

Author information

1
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
3
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
4
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.
5
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.

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.

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

PMID:
27916453
PMCID:
PMC5182147
DOI:
10.1016/j.neuron.2016.11.007
[Indexed for MEDLINE]
Free PMC Article

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