A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity

Abstract

BackgroundSelf-injurious behaviors (SIBs) are devastating traits in autism spectrum disorder (ASD). Although deficits in pain sensation might be one of the contributing factors underlying the development of SIBs, the mechanisms have yet to be addressed. Recently, the Shank2 synaptic protein has been considered to be a key component in ASD, and mutations of SHANK2 gene induce the dysfunction of N-methyl-D-aspartate (NMDA) receptors, suggesting a link between Shank2 and NMDA receptors in ASD. Given that spinal NMDA receptors play a pivotal role in pain hypersensitivity, we investigated the possible role of Shank2 in nociceptive hypersensitivity by examining changes in spontaneous pain following intrathecal NMDA injection in Shank2−/− (Shank2 knock-out, KO) mice.ResultsIntrathecal NMDA injection evoked spontaneous nociceptive behaviors. These NMDA-induced nociceptive responses were significantly reduced in Shank2 KO mice. We also observed a significant decrease of NMDA currents in the spinal dorsal horn of Shank2 KO mice. Subsequently, we examined whether mitogen-activated protein kinase or AKT signaling is involved in this reduced pain behavior in Shank2 KO mice because the NMDA receptor is closely related to these signaling molecules. Western blotting and immunohistochemistry revealed that spinally administered NMDA increased the expression of a phosphorylated form of extracellular signal-regulated kinase (p-ERK) which was significantly reduced in Shank2 KO mice. However, p38, JNK, or AKT were not changed by NMDA administration. The ERK inhibitor, PD98059, decreased NMDA-induced spontaneous pain behaviors in a dose-dependent manner in wild-type mice. Moreover, it was found that the NMDA-induced increase in p-ERK was primarily colocalized with Shank2 proteins in the spinal cord dorsal horn.ConclusionShank2 protein is involved in spinal NMDA receptor-mediated pain, and mutations of Shank2 may suppress NMDA-ERK signaling in spinal pain transmission. This study provides new clues into the mechanisms underlying pain deficits associated with SIB and deserves further study in patients with ASD.

RETRACTED: Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling

“…The SHANK family of master scaffolding proteins include three members, that is SHANK1, 2 and 3. SHANK family proteins have been linked to Autistic Spectrum Disorder ( Lim et al, 1999 ; Mei et al, 2016 ; Monteiro and Feng, 2017 ; Yoon et al, 2017 ). Mutations in genes encoding SHANK family proteins (SHANK1, 2 and 3) often result in marked behavioural phenotypes in mice ( Mameza et al, 2013 ; Schmeisser et al, 2012 ; Won et al, 2012 ), such as an increase in repetitive routines, altered social behaviour and anxiety-like phenotypes.…”

Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2−/− Mice

“…More recently, studies on mice lacking Shank2 in the whole brain or specific cell types have further enhanced our understanding of the normal functions of Shank2 as well as ASDrelated pathophysiology (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). For example, mice lacking exons 6-7 and exon 7of Shank2 display autistic-like behavioral abnormalities that are associated with altered N-methyl-Daspartate receptor (NMDAR) function (37,38).…”

Shank2 expression identifies a subpopulation of glycinergic interneurons involved in nociception and altered in an autism mouse model

“…Thus, depending on the acute or chronic phase and on the type of noxious stimulus, loss of Shank2 may result in increased or decreased sensitivity. Interestingly, Shank2-KO mice have been also reported to display a reduced sensitivity to the nociceptive response evoked by intrathecal injection of NMDA (Yoon et al, 2017). Since this procedure does not selectively activate one subpopulation of neurons, it is not possible to explain it in circuit terms.…”

“…Shank2-KO mice (obtained by targeting exon-6 and exon-7; Schmeisser et al, 2012;Won et al, 2012) display reduced social interaction, increased anxiety and compulsive grooming and are considered a bona fide mouse model of ASD. Recent work has suggested that Shank2-KO mice may display abnormal nociception due to alteration of spinal cord circuits (Yoon et al, 2017). Once again the neuronal subpopulations and the circuit architectural features responsible for such phenotype remain to be investigated.…”