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.

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Citation

Published Version (Please cite this version)

10.1016/j.neuron.2016.11.007

Publication Info

Han, Qingjian, Yong Ho Kim, Xiaoming Wang, Di Liu, Zhi-Jun Zhang, Alexandra L Bey, Mark Lay, Wonseok Chang, et al. (2016). SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons. Neuron, 92(6). pp. 1279–1293. 10.1016/j.neuron.2016.11.007 Retrieved from https://hdl.handle.net/10161/13678.

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Scholars@Duke

Bey

Alexandra L Bey

Assistant Professor of Psychiatry and Behavioral Sciences

Dr. Alexandra Bey holds both an M.D. and a PhD in Neurobiology. She serves as a Child Psychiatrist in the Duke Autism Clinic and is a valued member of the Duke University School of Medicine's Department of Psychiatry and Behavioral Sciences. Within the Division of Child and Family Mental Health and Community Psychiatry, Dr. Bey’s research and clinical career is dedicated to improving the lives of those with neurodevelopmental disorders. Her overarching research goal is to develop objective, relevant biomarkers to allow for more effective development and testing of novel therapies and to conduct translational research across preclinical models and in individuals with neurodevelopmental differences.

Ji

Ru-Rong Ji

Distinguished Professor of Anesthesiology, in the School of Medicine

I have been doing neuroscience and pain research for over 25 years in multiple academic institutes, including Duke University (2012-current), Harvard Medical School (1998-2012), Johns Hopkins Medical School, Karolinska Institute, and Peking University. The long-term goal of my lab is to identify molecular and cellular mechanisms that underlie the induction and resolution of pathological pain and develop novel pain therapeutics that can target these mechanisms, with specific focus on neuroimmune interactions. We are interested in the following scientific questions. (1) How does inflammation induce and resolve pain via immune cell interaction with primary sensory neurons? (2) How does neuroinflammation drive chronic pain via activation of glial cells in the CNS (microglia and astrocytes) and PNS (satellite glial cells) and regulation of sensory neuron plasticity (peripheral sensitization) and spinal cord synaptic plasticity (central sensitization)? (3) How do specialized pro-resolution mediators (SPMs, e.g., resolvins, protectins, and maresins) control pain via GPCR signaling? (4) How do immunotherapies through the PD-L1/PD-1 and STING/IFN pathways regulate pain, cognition, and neuronal activities? (5) How do secreted miRNAs regulate pain and itch via direct activation of surface receptors and ion channels? (6) How do nerve terminals interact with cancers in chronic pain and itch? (7) How do Toll-like receptors (TLR) in primary sensory neurons sense danger signals and regulate pain and itch? (8) How do regenerative approaches such as autologous conditioned serum (ACS) and bone marrow stromal cells (MSCs) produce long-term pain relief via secreting anti-inflammatory factors and exosomes? We employ a multidisciplinary approach that covers in vitro, ex vivo, and in vivo studies for animal behaviors, electrophysiology, molecular biology, cell biology, and transgenic animals. We have identified numerous therapeutic targets and filed many patents for translational studies. As the Director of the Center for Translational Pain Medicine (CTPM) and a highly cited researcher (Cross Field, Clarivate), I have both administrative and scientific leadership for successful completion of many research projects. 


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