Prenatal Valproic Acid Exposure and Autism Spectrum Disorder: An Integrative Review of Developmental Neurotoxicity Mechanisms and Animal Models
##article.authors##
- Asumi Kubo Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
- Sara Kamiya Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
- Koki Higuchi Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
- Kenyu Nakamura Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
- Sae Sanaka Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
-
Tetsuya Sasaki
Laboratory of Anatomy and Neuroscience, Department of Biomedical Sciences, Institute of Medicine, University of Tsukuba
https://orcid.org/0000-0002-7723-4417
https://researchmap.jp/tsasak
DOI:
https://doi.org/10.51094/jxiv.905Keywords:
Autism Spectrum Disorder, Brain Organoids, DOHaD Hypothesis, Environmental Factors, Valproic AcidAbstract
The prevalence of autism spectrum disorder (ASD) has been increasing, with recent estimates suggesting that 2.7% of children in the U.S. are diagnosed with ASD. Among environmental risk factors, prenatal exposure to valproic acid (VPA), an antiepileptic drug, has been shown to increase ASD risk. This review provides an integrative discussion of the association between VPA exposure and ASD, focusing on developmental neurotoxicity mechanisms and animal models. VPA's neurotoxicity affects epigenetic modifications, neural stem cell proliferation and differentiation, synaptogenesis, and neurotransmitter systems. These changes may underlie behavioral abnormalities and neurological features observed in ASD. Animal models exposed to VPA exhibit ASD-like behaviors and neurological changes, contributing to our understanding of ASD pathomechanisms. While environmental factors like VPA contribute to only a fraction of ASD cases, their study is crucial for identifying preventable risk factors. Future research should elucidate genetic-environmental interactions, advance epigenetics research, analyze time- and dose-dependent effects of environmental factors, integrate findings from animal models with human studies, apply findings to personalized medicine, and develop novel therapies. These efforts aim to enhance our understanding of ASD's complex pathomechanisms, potentially leading to effective prevention and treatment methods.
Conflicts of Interest Disclosure
The authors declare that they have no competing interests.Downloads *Displays the aggregated results up to the previous day.
References
Gangopadhyay M. DSM-5-TR® self-exam questions. Muskin PR, Dickerman AL, Drysdale A, Holderness CC, editors. Arlington, TX: American Psychiatric Association Publishing; 2023. 488 p.
Christensen DL, Braun KVN, Baio J, Bilder D, Charles J, Constantino JN, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ. 2018 Nov 16;65(13):1–23.
Bai D, Yip BHK, Windham GC, Sourander A, Francis R, Yoffe R, et al. Association of genetic and environmental factors with autism in a 5-country cohort. JAMA Psychiatry. 2019 Oct 1;76(10):1035–43.
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013 Apr 24;309(16):1696–703.
Christianson AL, Chesler N, Kromberg JG. Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol. 1994 Apr;36(4):361–9.
Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001 Sep;276(39):36734–41.
Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16659–64.
Juliandi B, Abematsu M, Nakashima K. Epigenetic regulation in neural stem cell differentiation. Dev Growth Differ. 2010 Aug;52(6):493–504.
Fujimura K, Mitsuhashi T, Shibata S, Shimozato S, Takahashi T. In utero exposure to valproic acid induces neocortical dysgenesis via dysregulation of neural progenitor cell proliferation/differentiation. J Neurosci. 2016 Oct 19;36(42):10908–19.
Uchino S, Hirasawa T, Tabata H, Gonda Y, Waga C, Ondo Y, et al. Inhibition of N-methyl-D-aspartate receptor activity resulted in aberrant neuronal migration caused by delayed morphological development in the mouse neocortex. Neuroscience. 2010 Aug 25;169(2):609–18.
Kumamaru E, Egashira Y, Takenaka R, Takamori S. Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons. Neurosci Lett. 2014 May 21;569:142–7.
Fukuchi M, Nii T, Ishimaru N, Minamino A, Hara D, Takasaki I, et al. Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neurosci Res. 2009 Sep;65(1):35–43.
Kazlauskas N, Campolongo M, Lucchina L, Zappala C, Depino AM. Postnatal behavioral and inflammatory alterations in female pups prenatally exposed to valproic acid. Psychoneuroendocrinology. 2016 Oct;72:11–21.
Sanagi T, Sasaki T, Nakagaki K, Minamimoto T, Kohsaka S, Ichinohe N. Segmented Iba1-positive processes of microglia in autism model marmosets. Front Cell Neurosci. 2019 Jul 30;13:344.
Lepko T, Pusch M, Müller T, Schulte D, Ehses J, Kiebler M, et al. Choroid plexus-derived miR-204 regulates the number of quiescent neural stem cells in the adult brain. EMBO J. 2019 Sep 2;38(17):e100481.
Sabers A, Bertelsen FCB, Scheel-Krüger J, Nyengaard JR, Møller A. Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism. Neurosci Lett. 2014 Sep 19;580:12–6.
Ingram JL, Peckham SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol. 2000 May;22(3):319–24.
Contestabile A, Greco B, Ghezzi D, Tucci V, Benfenati F, Gasparini L. Lithium rescues synaptic plasticity and memory in Down syndrome mice. J Clin Invest. 2013 Jan;123(1):348–61.
Rinaldi T, Kulangara K, Antoniello K, Markram H. Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13501–6.
Kim KC, Kim P, Go HS, Choi CS, Yang S-I, Cheong JH, et al. The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol Lett. 2011 Mar 5;201(2):137–42.
佐田文宏/福岡秀輿, editor. DOHaD 先制医療への展開. 金原出版株式会社; 2023年5月10日.
Kolozsi E, Mackenzie RN, Roullet FI, deCatanzaro D, Foster JA. Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience. 2009 Nov 10;163(4):1201–10.
Schaafsma SM, Pfaff DW. Etiologies underlying sex differences in Autism Spectrum Disorders. Front Neuroendocrinol. 2014 Aug;35(3):255–71.
Schneider Gasser EM, Schaer R, Mueller FS, Bernhardt AC, Lin H-Y, Arias-Reyes C, et al. Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function. Transl Psychiatry. 2024 Jul 16;14(1):289.
Roullet FI, Lai JKY, Foster JA. In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol. 2013 Mar;36:47–56.
Yasue M, Nakagami A, Banno T, Nakagaki K, Ichinohe N, Kawai N. Indifference of marmosets with prenatal valproate exposure to third-party non-reciprocal interactions with otherwise avoided non-reciprocal individuals. Behav Brain Res. 2015 Oct 1;292:323–6.
Mimura K, Oga T, Sasaki T, Nakagaki K, Sato C, Sumida K, et al. Abnormal axon guidance signals and reduced interhemispheric connection via anterior commissure in neonates of marmoset ASD model. Neuroimage. 2019 Jul 15;195:243–51.
Schneider T, Przewłocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology. 2005 Jan;30(1):80–9.
Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TPL, Siegel SJ. Validating γ oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010 Dec 15;68(12):1100–6.
Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology. 2008 Mar;33(4):901–12.
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 Feb;16(1):91–103.
Gogolla N, Leblanc JJ, Quast KB, Südhof TC, Fagiolini M, Hensch TK. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord. 2009 Jun;1(2):172–81.
Narita M, Oyabu A, Imura Y, Kamada N, Yokoyama T, Tano K, et al. Nonexploratory movement and behavioral alterations in a thalidomide or valproic acid-induced autism model rat. Neurosci Res. 2010 Jan;66(1):2–6.
Bronzuoli MR, Facchinetti R, Ingrassia D, Sarvadio M, Schiavi S, Steardo L, et al. Neuroglia in the autistic brain: evidence from a preclinical model. Mol Autism. 2018 Dec 27;9(1):66.
Patterson PH. Maternal infection and immune involvement in autism. Trends Mol Med. 2011 Jul;17(7):389–94.
Choi GB, Yim YS, Wong H, Kim S, Kim H, Kim SV, et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science. 2016 Feb 26;351(6276):933–9.
Servadio M, Vanderschuren LJMJ, Trezza V. Modeling autism-relevant behavioral phenotypes in rats and mice: Do “autistic” rodents exist? Behav Pharmacol. 2015 Sep;26(6):522–40.
Oskvig DB, Elkahloun AG, Johnson KR, Phillips TM, Herkenham M. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav Immun. 2012 May;26(4):623–34.
Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297–302.
Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun. 2012 May;26(4):607–16.
Smith SEP, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007 Oct 3;27(40):10695–702.
Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, et al. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science. 2013 Mar 1;339(6123):1095–9.
Coiro P, Padmashri R, Suresh A, Spartz E, Pendyala G, Chou S, et al. Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders. Brain Behav Immun. 2015 Nov;50:249–58.
Sztainberg Y, Zoghbi HY. Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci. 2016 Oct 26;19(11):1408–17.
Tick B, Bolton P, Happé F, Rutter M, Rijsdijk F. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J Child Psychol Psychiatry. 2016 May;57(5):585–95.
Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman C, Larsson H, Reichenberg A. The heritability of autism spectrum disorder. JAMA. 2017 Sep 26;318(12):1182.
Jiang H-Y, Xu L-L, Shao L, Xia R-M, Yu Z-H, Ling Z-X, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun. 2016 Nov;58:165–72.
Yasuda Y, Matsumoto J, Miura K, Hasegawa N, Hashimoto R. Genetics of autism spectrum disorders and future direction. J Hum Genet. 2023 Mar;68(3):193–7.
Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci. 2011 Sep;15(9):409–16.
LaSalle JM. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J Hum Genet. 2013 Jul;58(7):396–401.
Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism. Exp Neurol. 2018 Jan;299(Pt A):217–27.
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell. 2016 May 19;165(5):1238–54.
Zhong S, Zhang S, Fan X, Wu Q, Yan L, Dong J, et al. A single-cell RNA-seq survey of the developmental landscape of the human prefrontal cortex. Nature. 2018 Mar 22;555(7697):524–8.
Marton RM, Pașca SP. Organoid and assembloid technologies for investigating cellular crosstalk in human brain development and disease. Trends Cell Biol. 2020 Feb;30(2):133–43.
Trujillo CA, Gao R, Negraes PD, Gu J, Buchanan J, Preissl S, et al. Complex oscillatory waves emerging from cortical organoids model early human brain network development. Cell Stem Cell. 2019 Oct 3;25(4):558-569.e7.
Park SE, Georgescu A, Huh D. Organoids-on-a-chip. Science. 2019 Jun 7;364(6444):960–5.
Brassard JA, Lutolf MP. Engineering stem cell self-organization to build better organoids. Cell Stem Cell. 2019 Jun 6;24(6):860–76.
Downloads
Posted
Submitted: 2024-09-15 14:34:30 UTC
Published: 2024-09-19 00:48:43 UTC
License
Copyright (c) 2024
Asumi Kubo
Sara Kamiya
Koki Higuchi
Kenyu Nakamura
Sae Sanaka
Tetsuya Sasaki
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
