%0 Journal Article %T SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice %+ Universität Ulm - Ulm University [Ulm, Allemagne] %+ Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré] %+ Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)) %+ German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) %A Lutz, Anne-Kathrin %A Pérez Arévalo, Andrea %A Ioannidis, Valentin %A Stirmlinger, Nadine %A Demestre, Maria %A Delorme, Richard %A Bourgeron, Thomas %A Boeckers, Tobias, M %Z TMB was supported by the DFG [Project-ID 251293561 – Collaborative Research Center (CRC) 1149], Else Kröner Foundation, and receives 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. %< avec comité de lecture %@ 1662-5099 %J Frontiers in Molecular Neuroscience %I Frontiers Media %V 14 %P 773571 %8 2021-11-26 %D 2021 %R 10.3389/fnmol.2021.773571 %M 34899182 %K SHANK2 %K hiPSCs %K ERK1/2 %K neurodevelopment %K ASD %Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]Journal articles %X SHANK2 (ProSAP1) is a postsynaptic scaffolding protein of excitatory synapses in the central nervous system and implicated in the development of autism spectrum disorders (ASD). Patients with mutations in SHANK2 show autism-like behaviors, developmental delay, and intellectual disability. We generated human induced pluripotent stem cells (hiPSC) from a patient carrying a heterozygous deletion of SHANK2 and from the unaffected parents. In patient hiPSCs and derived neurons SHANK2 mRNA and protein expression was reduced. During neuronal maturation, a reduction in growth cone size and a transient increase in neuronal soma size were observed. Neuronal proliferation was increased, and apoptosis was decreased in young and mature neurons. Additionally, mature patient hiPSC-derived neurons showed dysregulated excitatory signaling and a decrease of a broad range of signaling molecules of the ERK-MAP kinase pathway. These findings could be confirmed in brain samples from Shank2 (−/−) mice, which also showed decreased mGluR5 and phospho-ERK1/2 expression. Our study broadens the current knowledge of SHANK2-related ASD. We highlight the importance of excitatory-inhibitory balance and mGluR5 dysregulation with disturbed downstream ERK1/2 signaling in ASD, which provides possible future therapeutic strategies for SHANK2-related ASD. %G English %2 https://pasteur.hal.science/pasteur-04069472/document %2 https://pasteur.hal.science/pasteur-04069472/file/fnmol-14-773571.pdf %L pasteur-04069472 %U https://pasteur.hal.science/pasteur-04069472 %~ PASTEUR %~ CNRS %~ APHP %~ OPENAIRE %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ UP-SCIENCES %~ HUM-GEN-COGN-FUN %~ PASTEUR_UMR3571