Un rôle critique des protéines Shank2 spinales dans l'hypersensibilité à la douleur induite par NMDA

Aperçu: G.M.

Les comportements d'auto-mutilations (SIB) sont des traits dévastateurs du trouble du spectre de l"autisme (TSA). Bien que les déficits de la sensation de douleur puissent être l'un des facteurs qui sous-tendent le développement des SIB, les mécanismes n'ont pas encore été abordés.

La protéine synaptique Shank2 a été considérée comme un composant clé dans le TSA, et les mutations du gène SHANK2 induisent le dysfonctionnement des récepteurs N-méthyl-D-aspartate (NMDA), suggérant un lien entre les récepteurs Shank2 et NMDA dans les TSA, récepteurs qui jouent un rôle central dans l'hypersensibilité à la douleur.La protéine Shank2 est impliquée dans la douleur médiée par le récepteur NMDA spinale, et les mutations de Shank2 peuvent supprimer la signalisation NMDA-ERK dans la transmission de la douleur spinale.

Mol Pain. 2017 Jan;13:1744806916688902. doi: 10.1177/1744806916688902.

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

Yoon SY^1,2, Kwon SG³, Kim YH^1,2,4, Yeo JH³, Ko HG⁵, Roh DH³, Kaang BK^5,6, Beitz AJ⁷, Lee JH^8,9, Oh SB^1,2.

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Abstract

Background Self-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 S hank2-/- ( Shank2 knock-out, KO) mice. Results Intrathecal 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. Conclusion Shank2 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.

PMID: 28326932

DOI: 10.1177/1744806916688902