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Molecular Autism
Published in: Molecular Autism 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Yuta Hara, Yukio Ago, Erika Takano, Shigeru Hasebe, Takanobu Nakazawa, Hitoshi Hashimoto, Toshio Matsuda, Kazuhiro Takuma

Published in: Molecular Autism | Issue 1/2017

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Abstract

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.
Literature
1.
Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology. 2005;30(1):80–9.CrossRefPubMed
2.
Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord. 2006;36(6):779–93.CrossRefPubMed
3.
Roullet FI, Lai JK, Foster JA. In utero exposure to valproic acid and autism—a current review of clinical and animal studies. Neurotoxicol Teratol. 2013;36:47–56.CrossRefPubMed
4.
Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol. 2013;16(1):91–103.CrossRefPubMed
5.
Takuma K, Hara Y, Kataoka S, Kawanai T, Maeda Y, Watanabe R, et al. Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism. Pharmacol Biochem Behav. 2014;126:43–9.CrossRefPubMed
6.
Hara Y, Maeda Y, Kataoka S, Ago Y, Takuma K, Matsuda T. Effect of prenatal valproic acid exposure on cortical morphology in female mice. J Pharmacol Sci. 2012;118(4):543–6.CrossRefPubMed
7.
Huntzinger E, Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet. 2011;12(2):99–110.CrossRefPubMed
8.
Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13(4):271–82.PubMed
9.
10.
Sun AX, Crabtree GR, Yoo AS. MicroRNAs: regulators of neuronal fate. Curr Opin Cell Biol. 2013;25(2):215–21.CrossRefPubMed
11.
12.
13.
Geaghan M, Cairns MJ. MicroRNA and posttranscriptional dysregulation in psychiatry. Biol Psychiatry. 2015;78(4):231–9.CrossRefPubMed
14.
Wu H, Tao J, Chen PJ, Shahab A, Ge W, Hart RP, et al. Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2010;107(42):18161–6.CrossRefPubMedPubMedCentral
15.
Mellios N, Woodson J, Garcia RI, Crawford B, Sharma J, Sheridan SD, et al. β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2014;111(27):9947–52.CrossRefPubMedPubMedCentral
16.
Liu T, Wan RP, Tang LJ, Liu SJ, Li HJ, Zhao QH, et al. A microRNA profile in Fmr1 knockout mice reveals microRNA expression alterations with possible roles in fragile X syndrome. Mol Neurobiol. 2015;51(3):1053–63.CrossRefPubMed
17.
Clovis YM, Enard W, Marinaro F, Huttner WB, De Pietri Tonelli D. Convergent repression of Foxp2 3′UTR by miR-9 and miR-132 in embryonic mouse neocortex: implications for radial migration of neurons. Development. 2012;139(18):3332–42.CrossRefPubMed
18.
Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, et al. An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci U S A. 2008;105(26):9093–8.CrossRefPubMedPubMedCentral
19.
Mellios N, Sugihara H, Castro J, Banerjee A, Le C, Kumar A, et al. miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity. Nat Neurosci. 2011;14(10):1240–2.CrossRefPubMedPubMedCentral
20.
Hancock ML, Preitner N, Quan J, Flanagan JG. MicroRNA-132 is enriched in developing axons, locally regulates Rasa1 mRNA, and promotes axon extension. J Neurosci. 2014;34(1):66–78.CrossRefPubMedPubMedCentral
21.
Yoshimura A, Numakawa T, Odaka H, Adachi N, Tamai Y, Kunugi H. Negative regulation of microRNA-132 in expression of synaptic proteins in neuronal differentiation of embryonic neural stem cells. Neurochem Int. 2016;97:26–33.CrossRefPubMed
22.
Miller BH, Zeier Z, Xi L, Lanz TA, Deng S, Strathmann J, et al. MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proc Natl Acad Sci U S A. 2012;109(8):3125–30.CrossRefPubMedPubMedCentral
23.
Walker RM, Rybka J, Anderson SM, Torrance HS, Boxall R, Sussmann JE, et al. Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder. J Psychiatr Res. 2015;62:48–55.CrossRefPubMedPubMedCentral
24.
Liu Y, Yang X, Zhao L, Zhang J, Li T, Ma X. Increased miR-132 level is associated with visual memory dysfunction in patients with depression. Neuropsychiatr Dis Treat. 2016;12:2905–11.CrossRefPubMedPubMedCentral
25.
De Pietri TD, Pulvers JN, Haffner C, Murchison EP, Hannon GJ, Huttner WB. miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development. 2008;135(23):3911–21.CrossRef
26.
Shibata M, Kurokawa D, Nakao H, Ohmura T, Aizawa S. MicroRNA-9 modulates Cajal-Retzius cell differentiation by suppressing Foxg1 expression in mouse medial pallium. J Neurosci. 2008;28(41):10415–21.CrossRefPubMed
27.
Hara Y, Takuma K, Takano E, Katashiba K, Taruta A, Higashino K, et al. Reduced prefrontal dopaminergic activity in valproic acid-treated mouse autism model. Behav Brain Res. 2015;289:39–47.CrossRefPubMed
28.
Hara Y, Ago Y, Taruta A, Katashiba K, Hasebe S, Takano E, et al. Improvement by methylphenidate and atomoxetine of social interaction deficits and recognition memory impairment in a mouse model of valproic acid-induced autism. Autism Res. 2016;9:926–39.CrossRefPubMed
29.
Vrana PB, Fossella JA, Matteson P, del Rio T, O’Neill MJ, Tilghman SM. Genetic and epigenetic incompatibilities underlie hybrid dysgenesis in Peromyscus. Nat Genet. 2000;25(1):120–4.CrossRefPubMed
30.
Müller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity. 1994;1(4):291–301.CrossRefPubMed
31.
Conaco C, Otto S, Han JJ, Mandel G. Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A. 2006;103(7):2422–7.CrossRefPubMedPubMedCentral
32.
Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, et al. microRNA modulation of circadian-clock period and entrainment. Neuron. 2007;54(5):813–29.CrossRefPubMedPubMedCentral
33.
Fiedler SD, Carletti MZ, Hong X, Christenson LK. Hormonal regulation of microRNA expression in periovulatory mouse mural granulosa cells. Biol Reprod. 2008;79(6):1030–7.CrossRefPubMedPubMedCentral
34.
Nakazawa T, Kikuchi M, Ishikawa M, Yamamori H, Nagayasu K, Matsumoto T, et al. Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine. Schizophr Res. 2017;181:75–82.CrossRefPubMed
35.
Nudelman AS, DiRocco DP, Lambert TJ, Garelick MG, Le J, Nathanson NM, et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus. 2010;20(4):492–8.PubMedPubMedCentral
36.
37.
Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A. 2005;102(45):16426–31.CrossRefPubMedPubMedCentral
38.
Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci. 2007;10(12):1513–4.CrossRefPubMed
39.
40.
Iyengar BR, Choudhary A, Sarangdhar MA, Venkatesh KV, Gadgil CJ, Pillai B. Non-coding RNA interact to regulate neuronal development and function. Front Cell Neurosci. 2014;8:47.CrossRefPubMedPubMedCentral
41.
Petri R, Malmevik J, Fasching L, Åkerblom M, Jakobsson J. miRNAs in brain development. Exp Cell Res. 2014;321(1):84–9.CrossRefPubMed
42.
Sun E, Shi Y. MicroRNAs: small molecules with big roles in neurodevelopment and diseases. Exp Neurol. 2015;268:46–53.CrossRefPubMed
43.
Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, et al. FXR1P but not FMRP regulates the levels of mammalian brain-specific microRNA-9 and microRNA-124. J Neurosci. 2011;31(39):13705–9.CrossRefPubMedPubMedCentral
44.
Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, et al. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008;9(3):153–61.CrossRefPubMed
45.
46.
Roullet FI, Wollaston L, Decatanzaro D, Foster JA. Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience. 2010;170(2):514–22.CrossRefPubMed
47.
Moldrich RX, Leanage G, She D, Dolan-Evans E, Nelson M, Reza N, Reutens DC. Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behav Brain Res. 2013;257:253–64.CrossRefPubMed
48.
Kawashima H, Numakawa T, Kumamaru E, Adachi N, Mizuno H, Ninomiya M, et al. Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression. Neuroscience. 2010;165(4):1301–11.CrossRefPubMed
49.
Numakawa T, Yamamoto N, Chiba S, Richards M, Ooshima Y, Kishi S, Hashido K, Adachi N, Kunugi H. Growth factors stimulate expression of neuronal and glial miR-132. Neurosci Lett. 2011;505(3):242–7.CrossRefPubMed
50.
Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet. 1980;5(1):67–83.CrossRefPubMed
51.
Dutta S, Reed RC. Functional half-life is a meaningful descriptor of steady-state pharmacokinetics of an extended-release formulation of a rapidly cleared drug: as shown by once-daily divalproex-ER. Clin Drug Investig. 2006;26(12):681–90.CrossRefPubMed
52.
Wanet A, Tacheny A, Arnould T, Renard P. miR-212/132 expression and functions: within and beyond the neuronal compartment. Nucleic Acids Res. 2012;40(11):4742–53.CrossRefPubMedPubMedCentral
53.
Nakazawa T, Kuriu T, Tezuka T, Umemori H, Okabe S, Yamamoto T. Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAP. J Neurochem. 2008;105(4):1384–93.CrossRefPubMed
54.
Vo NK, Cambronne XA, Goodman RH. MicroRNA pathways in neural development and plasticity. Curr Opin Neurobiol. 2010;20(4):457–65.CrossRefPubMed
55.
Guy J, Cheval H, Selfridge J, Bird A. The role of MeCP2 in the brain. Annu Rev Cell Dev Biol. 2011;27:631–52.CrossRefPubMed
56.
Siegel G, Saba R, Schratt G. microRNAs in neurons: manifold regulatory roles at the synapse. Curr Opin Genet Dev. 2011;21(4):491–7.CrossRefPubMed
57.
Cheng TL, Qiu Z. MeCP2: multifaceted roles in gene regulation and neural development. Neurosci Bull. 2014;30(4):601–9.CrossRefPubMed
58.
Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G, et al. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J Neurosci. 2012;32(29):10021–34.CrossRefPubMedPubMedCentral
59.
Rietveld L, Stuss DP, McPhee D, Delaney KR. Genotype-specific effects of Mecp2 loss-of-function on morphology of layer V pyramidal neurons in heterozygous female Rett syndrome model mice. Front Cell Neurosci. 2015;9:145.CrossRefPubMedPubMedCentral
60.
Dhar M, Zhu M, Impey S, Lambert TJ, Bland T, Karatsoreos IN, et al. Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP. Mol Endocrinol. 2014;28(7):1073–87.CrossRefPubMedPubMedCentral
61.
Kawanai T, Ago Y, Watanabe R, Inoue A, Taruta A, Onaka Y, et al. Prenatal exposure to histone deacetylase inhibitors affects gene expression of autism-related molecules and delays neuronal maturation. Neurochem Res. 2016;41(10):2574–84.CrossRefPubMed
62.
Nakamura T, Arima-Yoshida F, Sakaue F, Nasu-Nishimura Y, Takeda Y, Matsuura K, et al. PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking. Nat Commun. 2016;7:10861.CrossRefPubMedPubMedCentral
63.
Forero DA, van der Ven K, Callaerts P, Del-Favero J. miRNA genes and the brain: implications for psychiatric disorders. Hum Mutat. 2010;31(11):1195–204.CrossRefPubMed
64.
65.
Fregeac J, Colleaux L, Nguyen LS. The emerging roles of MicroRNAs in autism spectrum disorders. Neurosci Biobehav Rev. 2016;71:729–38.CrossRefPubMed
Metadata
Title
Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain
Authors
Yuta Hara
Yukio Ago
Erika Takano
Shigeru Hasebe
Takanobu Nakazawa
Hitoshi Hashimoto
Toshio Matsuda
Kazuhiro Takuma
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2017
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-017-0149-5

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