An EJC Factor RBM8a Regulates Anxiety Behaviors

Abstract

Neuroplasticity depends on the precise timing of gene expression, which requires accurate control of mRNA stability and rapid elimination of abnormal mRNA. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that ensures the speedy degradation of mRNAs carrying premature termination codons (PTCs). This mechanism relies on several key Exon Junction Complex (EJC) factors to distinguish PTCs from normal stop codons. NMD degrades not only aberrant transcripts carrying PTCs, but also normal transcripts harboring a normal stop codon [1]. Intriguingly, mutations in an NMD factor, Upf3b, have been found in patients with autism [2, 3]. A binding partner of Upf3b, RBM8a, is located in the 1q21.1 copy-number variation (CNV) associated with mental retardation, autism [4], schizophrenia [5], and microcephaly [6]. However, the functions of EJC factors and their roles in behavioral regulation are still elusive. RBM8a protein is a core component of the EJC that plays an important role in NMD. Recent genetic study indicated that RBM8a gain-of-function significantly associated with intellectual disability [7]. In this study we investigated the effect of RBM8a overexpression on affective behaviors in mice. Lentivirus expressing RBM8a was infused into the hippocampus of adult mice to conduct behavioral studies including social interaction, open field, elevated plus maze, and forced swimming tests. Our results showed that overexpression of RBM8a in the mouse dentate gyrus (DG) leads to increased anxiety-like behavior, abnormal social interaction and decreased immobile time in forced swimming test (FST). To examine the underlying mechanism, we found that overexpressing RBM8a in cultured primary neurons lead to significant higher frequency of miniature excitatory postsynaptic currents (mEPSCs). To explore the underlying mechanism of RBM8a mediated behavioral changes, RNA-immunoprecipitation (RNA-IP) detected that RBM8a binds to CaMK2, GluR1 and Egr1 mRNA, suggesting that RBM8a may target neuronal genes to regulate behaviors. This is the first study that demonstrates the key role of RBM8a on the emotional behaviors in mice. These results reveal new neural mechanisms by which NMD modulates behaviors and potentially provide a better understanding of pathophysiology underlying psychiatric disorders.

Uncovering Divergence of Rice Exon Junction Complex Core Heterodimer Gene Duplication Reveals Their Essential Role in Growth, Development, and Reproduction

“…MAGO and Y14 were recently shown to be involved in the eye development of Drosophila species (Ashton-Beaucage et al, 2010;Roignant and Treisman, 2010). MAGO regulates the proliferation and expansion of neural crest-derived melanocytes (Silver et al, 2013), whereas Y14 targets neuronal genes to regulate anxiety behaviors in mice (Alachkar et al, 2013). Therefore, these studies confirm the role of MAGO and Y14 genes in multiple related developmental roles in animal species.…”

DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

“…Primary culture of mouse hippocampal neurons was carried out as previously described [26]. In brief, hippocampal tissues were dissected from the brain of postnatal C57BL/6J mouse (postnatal day 1, within 24 hours after birth).…”

“…Stereotaxic injection of lentivirus was carried out according to procedures reported previously [26, 29]. Mice were anesthetized by intraperitoneal injection of Avertin (100 mg/kg) and then fixed in a stereotaxic apparatus (Stoelting Co. cat# 51725).…”

Nonsense-mediated mRNA decay: Inter-individual variability and human disease

“…Also associated with these conditions were copy number losses of genomic regions encompassing UPF3A and copy number gains in genomic regions encompassing SMG6 , EIF4A3 or RNPS1 . While the molecular pathology of these CNVs have not yet been investigated in humans, it is worth noting that overexpression of Rbm8a in a mouse model has been shown to increase anxiety-like behavior, impair social skills and decrease immobile time (Alachkar et al, 2013). Mice overexpressing Rbm8a also display enhanced frequency of miniature excitatory postsynaptic currents (Alachkar et al, 2013).…”

“…While the molecular pathology of these CNVs have not yet been investigated in humans, it is worth noting that overexpression of Rbm8a in a mouse model has been shown to increase anxiety-like behavior, impair social skills and decrease immobile time (Alachkar et al, 2013). Mice overexpressing Rbm8a also display enhanced frequency of miniature excitatory postsynaptic currents (Alachkar et al, 2013). Together, these studies suggest that either too much or too little of a given NMD factor can cause neurological or psychiatric disorders.…”