Dokument

Summary:
microRNAs (miRNAs) belong to a group of small non-coding RNAs that down regulates gene expression at the post-transcriptional level. The paternally imprinted placental mammal-specific miR379-410 cluster hosts 38 miRNAs. In the last decade, several members of the cluster have been shown to regulate synapse development and plasticity in mammals. Further, they have been implicated in a variety of diseases, including neurodevelopmental disorders. However, the potential involvement of these miRNAs in the control of complex behaviour in mammals, such as sociability, remains largely unknown. This is an important issue since aberrant synaptic dysfunction is thought to underlie neurodevelopmental diseases, such as autism spectrum disorder (ASD), characterized by deficits in social communication and interaction as well as restricted repetitive behaviour. This study aimed at the characterization of a constitutive knock-out (ko) mouse model that carries a deletion of the miR379-410 cluster. Extensive behavioural assays across the animals’ lifespan and cellular examinations of structural and functional properties of synapses were performed. Furthermore, transcriptome sequencing of adult miR379-410 ko hippocampi allowed the validation of potential direct target candidates of the miRNA cluster by using molecular and biochemical approaches. Mice deficient for the miR379-410 cluster displayed an anti-autistic-like phenotype, consisting of hypersocial behaviour, increased ultrasonic vocalizations (USVs) and reduced repetitive behaviour in the absence of cognitive impairments. Further, miR379-410 ko mice presented an anxiety phenotype over the lifespan. Along with the behavioural phenotype, miR379-410 ko mice showed increased excitatory synaptic transmission and spine density accompanied by an elevated expression of ionotropic glutamate receptor complex components in the hippocampus. Several of these components, identified by transcriptome profiling (Cnih2, Src, Prr7 and Dlgap3) could be validated as direct miR379-410 target genes. Taken together, the data obtained in this thesis describe for the first time a negative regulatory role of the miR379-410 cluster in social behaviour and the control of genes associated with excitatory synaptic function. Thus, interfering with miRNAs from the miR379-410 cluster could represent in the future a promising strategy for the treatment of neurodevelopmental disorders characterized by social dysfunction, such as ASD.

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