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Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice

Molecular Psychiatry volume 26, pages 1928–1944 (2021)Cite this article

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Abstract

Human mutations and haploinsufficiency of the SHANK family genes are associated with autism spectrum disorders (ASD) and intellectual disability (ID). Complex phenotypes have been also described in all mouse models of Shank mutations and deletions, consistent with the heterogeneity of the human phenotypes. However, the specific role of Shank proteins in synapse and neuronal functions remain to be elucidated. Here, we generated a new mouse model to investigate how simultaneously deletion of Shank1 and Shank3 affects brain development and behavior in mice. Shank1–Shank3 DKO mice showed a low survival rate, a developmental strong reduction in the activation of intracellular signaling pathways involving Akt, S6, ERK1/2, and eEF2 during development and a severe behavioral impairments. Our study suggests that Shank1 and Shank3 proteins are essential to developmentally regulate the activation of Akt and correlated intracellular pathways crucial for mammalian postnatal brain development and synaptic plasticity. Therefore, Akt function might represent a new therapeutic target for enhancing cognitive abilities of syndromic ASD patients.

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Fig. 1: Shank1 and Shank3 double mutation causes severe deficits in young (P22–25) mice.
Fig. 2: Shank1−/− Shank3−/− double KO mice exhibit syndromic ASDs-like behavior.
Fig. 3: Adult (P60) Shank1−/− Shank3−/− double KO mice have morphological and functional deficits.
Fig. 4: Chronic cotinine treatment during brain development rescues neuronal morphology of Shank1−/− Shank3−/− double KO mice.
Fig. 5: Chronic cotinine treatment during brain development rescues behavioral deficits of Shank1−/− Shank3−/− double KO mice.

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Acknowledgements

This work was supported by the Comitato Telethon Fondazione Onlus (grant no. GGP16131 to CV and GGP17176 to CS) and Regione Lombardia NeOn Progetto "NeOn" POR-FESR 2014–2020, ID 239047, CUP E47F17000000009 to CS and CV and Fondation Jérôme Lejeune (project #1638 to CS and project #1938 to CV). TMB is supported by the DFG (Project-ID 251293561—Collaborative Research Center (CRC) 1149), the Else Kröner Foundation and the project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI. Moreover, funding was received from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 847818—CANDY.

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Author notes

  1. These authors contributed equally: Adele Mossa, Jessica Pagano

Authors and Affiliations

  1. CNR Neuroscience Institute, Milan, Milano, Italy

    Adele Mossa, Jessica Pagano, Luisa Ponzoni, Stefania Beretta, Mariaelvina Sala, Carlo Sala & Chiara Verpelli

  2. University of Perugia, Department of Experimental Medicine, Perugia, Italy

    Alessandro Tozzi

  3. Università degli Studi di Milano, Department of Medical Biotechnology and Translational Medicine Milano, Milano, Italy

    Elena Vezzoli, Maura Francolini, Carlo Sala & Chiara Verpelli

  4. University of Perugia, Department of Medicine and Clinica Neurologica, Santa Maria della Misericordia Hospital, Perugia, Italy

    Miriam Sciaccaluga & Cinzia Costa

  5. Clinica Neurologica, Dipartimento di Neuroscienze, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy

    Paolo Calabresi

  6. Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany

    Tobias M. Boeckers

  7. DZNE, Ulm site, Ulm, Germany

    Tobias M. Boeckers

  8. NeuroMI Milan Center for Neuroscience, University of Milano-Bicocca, Milan, Italy

    Carlo Sala & Chiara Verpelli

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  1. Adele Mossa
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Contributions

AM, JP, LP, AT, EV, CC, and SB participated in the execution and analysis of experiments. AM, JP, MF, MS, PC, TMB, CS, and CV participated in the interpretation of the results. CS and CV designed the experiments and wrote the paper.

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Correspondence to Carlo Sala or Chiara Verpelli.

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Mossa, A., Pagano, J., Ponzoni, L. et al. Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice. Mol Psychiatry 26, 1928–1944 (2021). https://doi.org/10.1038/s41380-020-00979-x

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