SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice

Anne-Kathrin Lutz (1) , Andrea Pérez Arévalo (1) , Valentin Ioannidis (1) , Nadine Stirmlinger (1) , Maria Demestre (1) , Richard Delorme (2) , Thomas Bourgeron (3) , Tobias M Boeckers (4, 1)

1 Universität Ulm - Ulm University [Ulm, Allemagne]
2 Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré]
3 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
4 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen

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.

Mots clés: SHANK2; hiPSCs; ERK1/2; neurodevelopment; ASD

Domaines: Neurosciences [q-bio.NC]

Anne-Kathrin Lutz, Andrea Pérez Arévalo, Valentin Ioannidis, Nadine Stirmlinger, Maria Demestre, et al.. SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice. Frontiers in Molecular Neuroscience, 2021, 14, pp.773571. ⟨10.3389/fnmol.2021.773571⟩. ⟨pasteur-04069472⟩