Scientists say they have discovered a microRNA (miRNA) cluster that regulates synaptic strength and is involved in the control of social behavior in mammals. The researchers believe their discovery may point to new therapeutic strategies for the treatment of social deficits in neurodevelopmental disorders such as autism spectrum disorder or schizophrenia.

The team’s study (“A placental mammal‐specific miRNA cluster acts as a natural brake for sociability in mice”) appears in EMBO Reports.

“Aberrant synaptic function is thought to underlie social deficits in neurodevelopmental disorders such as autism and schizophrenia. Although miRNAs have been shown to regulate synapse development and plasticity, their potential involvement in the control of social behavior in mammals remains unexplored. Here, we show that deletion of the placental mammal‐specific miR379‐410 cluster in mice leads to hypersocial behavior, which is accompanied by increased excitatory synaptic transmission, and exaggerated expression of ionotropic glutamate receptor complexes in the hippocampus,” write the investigators.

“Bioinformatic analyses further allowed us to identify five ‘hub’ miRNAs whose deletion accounts largely for the upregulation of excitatory synaptic genes observed, including Cnih2, Dlgap3, Prr7, and Src. Thus, the miR379‐410 cluster acts as 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.”

In their work at the University of Marburg, Germany, and later on at ETH Zurich, Switzerland, the research group of Gerhard Schratt, Ph.D., and other laboratories have uncovered that a cluster of 38 miRNAs, termed miR379-410, plays an important role in neural development. Moreover, several hints pointed to the possibility that miR379-410 is involved in social behavior.

Dr. Schratt and colleagues investigated this option in more detail and found that miR379-410 indeed regulates sociability in the brain of mice. The study opens up a new perspective on the molecular mechanisms behind social behavior. The researchers first observed that mice lacking a functional miR379-410 complex were more sociable than their littermates, indicating that miR379-410 functions to restrict sociability in healthy animals. Further investigation showed that neurons in the hippocampus of the brain in mice lacking miR379-410 formed more connections and were more likely to transmit electrical signals.

“Our study indicates that miR379-410 plays an important role in the development of neural circuitries that control social behavior,” explained Dr. Schratt.

At the molecular level, the miR379-410 complex targets thousands of genes, among them many that were known to function in regulating synaptic transmission. Moreover, a small subgroup of only five miRNAs from the cluster might explain to a large extent the upregulation of key synaptic proteins. These proteins are involved in a process termed homeostatic synaptic downscaling—a feedback loop that kicks in when the brain becomes overactive because synaptic contacts are too strong.

While the current study uses mice as a model organism, there are indications that the miR379-410 complex is also involved in the regulation of social behavior in humans. For example, several miR-379-410 members are dysregulated in the blood and brain of patients with neurodevelopmental disorders that affect social behavior, such as schizophrenia or autism spectrum disorder.

“We hope that our study will contribute to the development of treatments to ameliorate social deficits in neuropsychiatric conditions in the future,” said Dr. Schratt.

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