Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain

Abstract

BackgroundMicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain.ResultsPrenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain.ConclusionsThese findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.

Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells

“…Accumulating evidences demonstrated that microRNA plays crucial role in neural development [ 66 67 ], and perturbation of microRNA is involved in neurodevelopmental disorders, such as ASD and fragile X-syndrome [ 68 69 70 ]. MiR-132 is one of the dominantly expressed microRNA in brain [ 71 ], and it represses MeCP2 levels by binding its miRNA recognition element (MRE) with MeCP2 3′UTR thus inhibits MeCP2 levels [ 72 ]. Interestingly, prenatal exposure to VPA displayed enhanced miR-132 whereas decrease of MeCP2 mRNA in embryonic brain [ 71 ].…”

Maternal immune activation alters brain microRNA expression in mouse offspring

“…Hara et al. reported conflicting results; prenatal exposure to valproic acid upregulated miR‐132‐5p expression in the embryonic mouse brain 33. However, the effect of miR‐132‐5p upregulation was transient, lasting only 18–24 h after valproic acid exposure, which might explain the opposite direction of miR‐132‐5p dysregulation, compared to other studies in human cases 8, 9…”

“…Furthermore, IL‐17a, produced by T helper 17 cells, was found to act downstream of IL‐6, leading to abnormal cortical development and behavioral phenotypes in MIA offspring 15. Previous studies examined miRNA levels in the embryonic or adult brain of ASD mice 32, 33. It should be noted that this is the first study to analyze the whole‐brain expression of ASD‐associated mRNAs and miRNAs at the transcriptome level, particularly in the early postnatal mouse brain, which is the main strength of this study.…”

Abnormalities in interactions of Rho GTPases with scaffolding proteins contribute to neurodevelopmental disorders

“…In particular, Ras signaling pathways known to be involved in regulating dendrite and spine plasticity are associated with autism spectrum disorders (Ye & Carew, ). In a recent study, it was demonstrated that prenatal valproic acid exposure, the model of autism disorder, decreased mRNA levels of the Rho GTPase‐activating protein p250 GAP (Hara et al, ). It is known that GTPases Cdc42 and Rac are involved in the immunodeficiency disorder Wiskott‐Aldrich syndrome.…”