miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice

• Published in: Cell reports (Cambridge) 2024-07, Vol.43 (7), p.114429, Article 114429
• Main Authors: Narayanan, Ramanathan, Levone, Brunno Rocha, Winterer, Jochen, Nanda, Prakruti, Müller, Alexander, Lobriglio, Thomas, Fiore, Roberto, Germain, Pierre-Luc, Mihailovich, Marija, Testa, Giuseppe, Schratt, Gerhard
• Format: Article
• Language: English
• Subjects: actomyosin; Actomyosin - metabolism; Animals; hippocampus; Hippocampus - metabolism; Humans; Induced Pluripotent Stem Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miR-379-410 cluster; Pyramidal Cells - metabolism; rho-Associated Kinases - metabolism; ROCK; sociability; Social Behavior; Williams-Beuren syndrome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114429

Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA (miRNA) cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to larger dendritic spines, increased excitatory synaptic transmission, and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, is sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members are reciprocally dysregulated in isogenic human induced pluripotent stem cell (iPSC)-derived neurons harboring a deletion present in patients with Williams-Beuren syndrome, characterized by hypersocial behavior. Together, our results show an miRNA-actomyosin pathway involved in social behavior regulation. [Display omitted] •Hippocampal loss of a microRNA cluster causes hypersociability in adult male mice•Hypersociability is due to the induction of an actomyosin gene network in excitatory neurons•Downregulation of miRNA cluster is observed in a cellular model of Williams-Beuren syndrome Narayanan et al. describe a role for the placental-mammal-specific miR-379-410 cluster in the regulation of social behavior in adult male mice. Mechanistically, a specific subset of cluster microRNAs regulates the expression of an actomyosin network in neurons, which in turn controls the morphology and strength of excitatory synapses.