Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 6, Pages 1928-1944Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-020-00979-x
Keywords
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Funding
- Comitato Telethon Fondazione Onlus [GGP16131, GGP17176]
- Regione Lombardia NeOn Progetto NeOn POR-FESR 2014-2020 [239047, CUP E47F17000000009]
- Fondation Jerome Lejeune [1638, 1938]
- DFG [251293561, (CRC) 1149]
- Else Kroner Foundation
- Innovative Medicines Initiative 2 Joint Undertaking [777394]
- European Union
- EFPIA
- AUTISM SPEAKS, Autistica, SFARI
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Mutations in SHANK family genes in humans are associated with autism spectrum disorders and intellectual disability. A new mouse model with simultaneous deletion of Shank1 and Shank3 showed low survival rate, reduced activation of signaling pathways, and severe behavioral impairments, suggesting the importance of Shank proteins in postnatal brain development and synaptic plasticity.
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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