Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of <scp>NMDA</scp> receptor levels at axon terminals

Halbedl, Sonja; Schoen, Michael; Feiler, Marisa S.; Boeckers, Tobias M.; Schmeißer, Michael J.

doi:10.1111/jnc.13523

Cited by 41 publications

(34 citation statements)

References 40 publications

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“…Inflammation not only induces heat hyperalgesia but also increases TRPV1 expression in DRG neurons and axonal transport of TRPV1 to skin nerve terminals (Ji et al, 2002). SHANK3 is also present in axonal terminals and presynaptic components of hippocampal neurons (Halbedl et al, 2016), but the function of this presynaptic SHANK3 was not investigated in this study. Remarkably, deletion of the autism gene Mecp2 in DRG mechanosensory neurons results in loss of prespresynaptic inhibition in the spinal cord, tactile hypersensitivity, and behavioral phenotypes of ASD (Orefice et al, 2016).…”

Section: Discussionmentioning

confidence: 93%

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

Han

Kim

Wang

et al. 2016

Neuron

123

129

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SUMMARY Abnormal pain sensitivity is commonly associated with autism spectrum disorders (ASDs) and affects the life quality of ASD individual. 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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Section: Discussionmentioning

confidence: 93%

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

Han

Kim

Wang

et al. 2016

Neuron

123

129

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“…In this study we used target specific Shank antibodies which have been extensively characterized in a recent work (Halbedl et al, 2016 ) and were used in previous studies. For Shank1 we used NB300-167 from Novus (Schmeisser et al, 2012 ), for Shank2 we used the “ppI-SAM pab SA5192” antibody (Bockers et al, 1999 ; Schmeisser et al, 2012 ), for Shank3 we primarily used the “PRC pab” antibody (Schmeisser et al, 2012 ), and in one case (Supplementary Figure S4 ) the “Shank3 (C-term)” antibody (Bockmann et al, 2002 ) was used (Supplementary Figure S1A ).…”

Section: Resultsmentioning

confidence: 99%

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

Heise

Schroeder

Schoen

et al. 2016

Front. Cell. Neurosci.

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Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies.

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“…Mutations in Shank3 affect the neurexin-neuroligin transsynaptic pathway. Additionally, recently it has been published that Shank mRNA and protein can be detected on the axonal terminal of the neuronal growth cone colocalizing with various presynaptic proteins there [ 26 ]. Thus, during early neuronal development, it is possible that Shank3 also acts directly on actin signaling in the presynapse.…”

Section: Actin Dynamics At Synaptic Terminalsmentioning

confidence: 99%

Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies

Sarowar

Grabrucker

2016

Neural Plasticity

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Shank proteins (Shank1, Shank2, and Shank3) act as scaffolding molecules in the postsynaptic density of many excitatory neurons. Mutations in SHANK genes, in particular SHANK2 and SHANK3, lead to autism spectrum disorders (ASD) in both human and mouse models. Shank3 proteins are made of several domains—the Shank/ProSAP N-terminal (SPN) domain, ankyrin repeats, SH3 domain, PDZ domain, a proline-rich region, and the sterile alpha motif (SAM) domain. Via various binding partners of these domains, Shank3 is able to bind and interact with a wide range of proteins including modulators of small GTPases such as RICH2, a RhoGAP protein, and βPIX, a RhoGEF protein for Rac1 and Cdc42, actin binding proteins and actin modulators. Dysregulation of all isoforms of Shank proteins, but especially Shank3, leads to alterations in spine morphogenesis, shape, and activity of the synapse via altering actin dynamics. Therefore, here, we highlight the role of Shank proteins as modulators of small GTPases and, ultimately, actin dynamics, as found in multiple in vitro and in vivo models. The failure to mediate this regulatory role might present a shared mechanism in the pathophysiology of autism-associated mutations, which leads to dysregulation of spine morphogenesis and synaptic signaling.

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Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals

Cited by 41 publications

References 40 publications

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

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

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

Actin-Dependent Alterations of Dendritic Spine Morphology in Shankopathies

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