A placental mammal‐specific micro RNA cluster acts as a natural brake for sociability in mice

Abstract

Aberrant synaptic function is thought to underlie social deficits in neurodevelopmental disorders such as autism and schizophrenia. Although microRNAs have been shown to regulate synapse development and plasticity, their potential involvement in the control of social behaviour in mammals remains unexplored. Here, we show that deletion of the placental mammal‐specific miR379‐410 cluster in mice leads to hypersocial behaviour, which is accompanied by increased excitatory synaptic transmission, and exaggerated expression of ionotropic glutamate receptor complexes in the hippocampus. Bioinformatic analyses further allowed us to identify five “hub” microRNAs whose deletion accounts largely for the upregulation of excitatory synaptic genes observed, including Cnih2, Dlgap3, Prr7 and Src. Thus, the miR379‐410 cluster acts a natural brake for sociability, and interfering with specific members of this cluster could represent a therapeutic strategy for the treatment of social deficits in neurodevelopmental disorders.

Advanced paternal age as a risk factor for neurodevelopmental disorders: a translational study

“…Further, based on results from rodent studies, miR-132 and miR-134 (as part of the miR379-410 cluster) appear to play a particularly important role in the context of neurodevelopmental disorders, since they regulate neuronal development and synaptic plasticity, as well as cognitive and social behavior [34]. Recently, miR-132 dysregulation was shown to trigger anxiety-related behavior [35], while deletion of the miR379-410 cluster in mice promoted anxiety and sociability [36]. Together, these findings in animal models support the notion that the increased risk of de novo mutations and epigenetic changes associated with ongoing cell divisions of spermatogonia in the testes throughout reproductive life underlie the association between APA and ASD or SZ.…”

Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling

“…This finding indicates that our approach is able to identify functionally important miRNAs solely on the basis of differential expression analysis. On the other hand, our enrichment analysis identified an overrepresentation of several miRNA binding motifs in mRNAs that are specifically downregulated by PTX in the process compartment, such as the activity-regulated miR-132/212 34 , miR-24-3p, miR-125a-5p, as well as the miR-379-410 cluster 11 members miR-329-3p and miR-485-5p 35 . One miRNA that appears to be specifically active in dendrites during PTX-induced downscaling is miR-34c-5p, a member of the miR-34/449 family (Fig.…”

“…Gene Ontology enrichment analysis was performed using the TopGo algorithm (v.2.40.0) 54 , essentially as described previously in 35 .…”

Evidence for the Placenta-Brain Axis: Multi-Omic Kernel Aggregation Predicts Intellectual and Social Impairment in Children Born Extremely Preterm

“…LZTS2, another gene we found to be associated with IQ, is involved in regulating embryonic development by the Wnt signaling pathway [67,68]. Genetic and miRNA expression studies have linked LZTS2 to social impairment and ASD [69][70][71]. Furthermore, LZTS2 is bound by the Chromodomain Helicase DNA Binding Protein 8 gene (CHD8), which is associated with brain development in mice and neurodevelopmental disorders in humans [72][73][74].…”