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Published on: March 25, 2016
Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain
Yuta Hara1,2, Yukio Ago1,2, Erika Takano2
1Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan.
Background:
MicroRNAs, 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.
Results:
Prenatal 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.
Conclusions:
These 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.
Insights
Prenatal valproic acid (VPA) exposure increases miR-132 levels in the embryonic mouse brain, potentially contributing to autism spectrum disorder (ASD) traits. This study investigates early microRNA changes linked to VPA
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are crucial for brain development.
- Dysregulated miRNA levels are implicated in neurodevelopmental disorders like autism spectrum disorder (ASD).
- Prenatal exposure to valproic acid (VPA) is a known risk factor for ASD.
Purpose of the Study:
- To investigate the impact of prenatal VPA exposure on miRNA levels in the embryonic mouse brain.
- To identify specific miRNAs, particularly brain-specific ones, affected by VPA.
Main Methods:
- Mice were exposed to VPA prenatally at different embryonic stages (E12.5 and E14.5).
- Quantitative real-time PCR was used to measure miRNA and mRNA levels.
- RNA sequencing was performed to analyze global miRNA expression changes.
Main Results:
- Prenatal VPA exposure at E12.5 increased miR-132 levels in both male and female embryonic brains.
- VPA exposure at E12.5 also altered mRNA levels of neuronal activity markers (Arc, c-Fos, BDNF) and VPA-targeted genes (MECP2, p250GAP).
- RNA sequencing revealed broader changes in miRNA expression beyond miR-132.
Conclusions:
- Prenatal VPA exposure alters embryonic miRNA levels, including miR-132.
- These miRNA alterations may contribute to ASD-like behaviors and cortical pathologies associated with prenatal VPA exposure.
