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      Reduced acute nociception and chronic pain in Shank2 −/− mice

      brief-report
      Author(s): , PhD 1 , , DDS, PhD 2 , 3 , , PhD 4 , 5 , , PhD 1 , 5 ,
      Publication date (Electronic):
      Journal: Molecular Pain
      Publisher: SAGE Publications
      Keywords: Autism, pain, shank2, nociception

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          Abstract

          Autism spectrum disorder is a debilitating mental illness and social issue. Autism spectrum disorder patients suffer from social isolation, cognitive deficits, compulsive behavior, and sensory deficits, including hyposensitivity to pain. However, recent studies argued that autism spectrum disorder patients show physiological pain response and, in some cases, even extremely intense pain response to harmless stimulation. Recently, Shank gene family was reported as one of the genetic risk factors of autism spectrum disorder. Thus, in this study, we used Shank2 − / − (Shank2 knock-out, KO) mice to investigate the controversial pain sensitivity issue and found that Shank2 KO mice showed reduced tactile perception and analgesia to chronic pain.

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          Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin.

          S Naisbitt, E. Kim, J. TU … (1999)
          NMDA receptors are linked to intracellular cytoskeletal and signaling molecules via the PSD-95 protein complex. We report a novel family of postsynaptic density (PSD) proteins, termed Shank, that binds via its PDZ domain to the C terminus of PSD-95-associated protein GKAP. A ternary complex of Shank/GKAP/PSD-95 assembles in heterologous cells and can be coimmunoprecipitated from rat brain. Synaptic localization of Shank in neurons is inhibited by a GKAP splice variant that lacks the Shank-binding C terminus. In addition to its PDZ domain, Shank contains a proline-rich region that binds to cortactin and a SAM domain that mediates multimerization. Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor/PSD-95 complexes and coupling them to regulators of the actin cytoskeleton.
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            Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.

            Hyejung Won, Hye-Ryeon Lee, Heon Yung Gee … (2012)
            Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.
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              Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2.

              Michael Schmeisser, Elodie Ey, Stephanie Wegener … (2012)
              Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Pain
                Journal ID (iso-abbrev): Mol Pain
                Journal ID (publisher-id): MPX
                Journal ID (hwp): spmpx
                Title: Molecular Pain
                Publisher: SAGE Publications (Sage CA: Los Angeles, CA )
                ISSN (Electronic): 1744-8069
                Publication date (Electronic): 4 May 2016
                Publication date Collection: 2016
                Volume: 12
                Electronic Location Identifier: 1744806916647056
                Affiliations
                [1 ]Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea
                [2 ]Department of Brain and Cognitive Sciences, College of Natural Sciences, Pain Cognitive Function Research Center, Dental Research Institute
                [3 ]Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Korea
                [4 ]Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada
                [5 ]Center for Neuron and Disease, Frontier Institutes of Science and Technology, Xi’an Jiaotong University, Xi'an, China
                Author notes
                [*]Bong-Kiun Kaang, Department of Biological Sciences, Seoul National University, Building 504 Rm 202, 1 Gwanangno, Gwanak-gu, Seoul 08826, Korea. Email: kaang@ 123456snu.ac.kr
                Article
                Publisher ID: 10.1177_1744806916647056
                DOI: 10.1177/1744806916647056
                PMC ID: 4956181
                PubMed ID: 27145803
                SO-VID: 43de6bd7-e8da-4996-9d58-acc541a6a53a
                Copyright © © The Author(s) 2016
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 4 February 2016
                Date revision received : 12 March 2016
                Date accepted : 4 April 2016
                Categories
                Subject: Short Report
                Custom metadata
                cover-date January-December 2016

                ScienceOpen disciplines: Molecular medicine
                Keywords: autism,pain,shank2,nociception
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: autism, pain, shank2, nociception

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