Small RNA regulators of social behaviour in eutherian mammals

Abstract

Small non-coding miRNA appear to be vital in brain development and function by organising complex patterns of gene expression. These molecules are important for the regulation of synaptically localised mRNAs that encode proteins involved in neurotransmission and behaviour. In this issue of EMBO Reports, Lackinger et al [1] demonstrate that a large cluster of miRNAs, that emerged in placental mammals, functions as a repressor of social behaviour. This discovery has significant implications for our understanding of the brain, behaviour and in particular psychiatric syndromes, which have been shown to display alterations of these molecules.

Figure 1. Excitatory pyramidal neurons of the hippocampus under the influence of the miR379‐410 microRNA cluster

The human chromosome 14 is shown inside the nuclear membrane, with the region 14q32.2 expressing the polycistronic primary miRNA transcript Mirg. After cleavage by the microprocessor complex, the precursor miRNA “hairpins” from the cluster are exported into the cytoplasm and interact with proteins in the RNA‐induced silencing complex and their target transcripts. This complex is then able to recruit the CCR4_NOT complex promoting deadenylation (Pacman motif Y), decapping and degradation (Pacman motif X) of mRNAs via the exonuclease XRN1. This prevents the synthesis of target transcripts that encode the ionotropic glutamate receptor complex, leading to a reduction of synaptic neurotransmission and connectivity in circuits facilitating social behaviour. When the expression of the miR379‐410 microRNA cluster is reduced in psychiatric syndromes, or in a knockout mouse model, target transcripts escape post‐transcriptional gene regulation and are available to bind ribosomes and template protein synthesis, including the subunits of the ionotropic glutamate receptor complex. These become inserted into the post‐synaptic density and enhance synaptic neurotransmission.