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2000
Volume 24, Issue 10
  • ISSN: 1871-5273
  • E-ISSN: 1996-3181
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Abstract

Introduction

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic and environmental basis. It frequently causes social and communication deficits, as well as repetitive behaviours. Valproic acid (VPA) has been shown to induce autistic-like features in animal models when administered during critical development periods. However, not much is known about its effect on cells to replicate ASD characteristics .

Objective

This review explores VPA models to elucidate the molecular and morphological characteristics of ASD, emphasizing their potential and proposing directions for future research.

Methods

PubMed, SciELO, Embase, Web of Science, and Scopus databases were searched, and 11 studies were included after screening.

Results

The studies explored VPA's effects on various cell cultures, including human neural cell lines, primary adult neurons, and primary embryonic neurons. VPA was found to be neurotoxic in a dose- and time-dependent manner, with greater toxicity in immature and undifferentiated cells. , VPA can influence gene expression, increase oxidative stress, disrupt neurogenesis and synaptogenesis, affect the GABAergic system, and alter critical signaling pathways for brain development and cell differentiation, such as Wnt/β-catenin.

Conclusion

models provide valuable insights into the morpho-molecular alterations induced by VPA and their connection to ASD. These findings highlight the need for further research into VPA's cellular effects to deepen our understanding of its role in ASD pathology.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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References

  1. Diagnostic and statistical manual of mental disorders.5th edWashington, DCAmerican Psychiatric Association Publishing2022
     [Google Scholar]
  2. GuoZ. TangX. XiaoS. Systematic review and meta-analysis: Multimodal functional and anatomical neural alterations in autism spectrum disorder.Mol. Autism20241511610.1186/s13229‑024‑00593‑6 38576034
     [Google Scholar]
  3. RajabiP. NooriA.S. SargolzaeiJ. Autism spectrum disorder and various mechanisms behind it.Pharmacol. Biochem. Behav.202424517388710.1016/j.pbb.2024.173887 39378931
     [Google Scholar]
  4. DługoszA. WróblewskiM. BłaszakB. SzulcJ. The role of nutrition, oxidative stress, and trace elements in the pathophysiology of autism spectrum disorders.Int. J. Mol. Sci.202526280810.3390/ijms26020808 39859522
     [Google Scholar]
  5. LoveC. SominskyL. O’HelyM. BerkM. VuillerminP. DawsonS.L. Prenatal environmental risk factors for autism spectrum disorder and their potential mechanisms.BMC Med.202422139310.1186/s12916‑024‑03617‑3 39278907
     [Google Scholar]
  6. Data & statistics on autism spectrum disorder.Available from: https://www.cdc.gov/ncbddd/autism/data.html 2023
  7. Al-DewikN.I. AlsharshaniD. SamaraM. Risk factors diagnosis prognosis and treatment of autism.Front. Biosci.20202591682171710.2741/4873 32472753
     [Google Scholar]
  8. OstrowskiJ. ReligioniU. GellertB. Sytnik-CzetwertyńskiJ. PinkasJ. Autism spectrum disorders: Etiology, epidemiology, and challenges for public health.Med. Sci. Monit.202430e94416110.12659/MSM.944161 38833427
     [Google Scholar]
  9. ChenB. XuX. WangY. YangZ. LiuC. ZhangT. VPA-induced autism impairs memory ability through disturbing neural oscillatory patterns in offspring rats.Cogn. Neurodynamics20241841563157410.1007/s11571‑023‑09996‑2 39104704
     [Google Scholar]
  10. TianY. XiaoX. LiuW. TREM2 improves microglia function and synaptic development in autism spectrum disorders by regulating P38 MAPK signaling pathway.Mol. Brain20241711210.1186/s13041‑024‑01081‑x 38409127
     [Google Scholar]
  11. NicoliniC FahnestockM The valproic acid-induced rodent model of autism.Exp Neurol2018299Pt A2172710.1016/j.expneurol.2017.04.01728472621
     [Google Scholar]
  12. Angus-LeppanH. ArkellR. WatkinsL. HeaneyD. CooperP. ShankarR. New valproate regulations, informed choice and seizure risk.J. Neurol.202427185671568610.1007/s00415‑024‑12436‑8 38896265
     [Google Scholar]
  13. MariJ. DieckmannL.H.J. Prates-BaldezD. HaddadM. Rodrigues da SilvaN. KapczinskiF. The efficacy of valproate in acute mania, bipolar depression and maintenance therapy for bipolar disorder: An overview of systematic reviews with meta-analyses.BMJ Open20241411e08799910.1136/bmjopen‑2024‑087999 39500601
     [Google Scholar]
  14. Collins-YoderA. LowellJ. Valproic acid: Special considerations and targeted monitoring.J. Neurosci. Nurs.2017491566110.1097/JNN.0000000000000259 28060221
     [Google Scholar]
  15. ZhangL.Y. ZhangS.Y. WenR. ZhangT.N. YangN. Role of histone deacetylases and their inhibitors in neurological diseases.Pharmacol. Res.202420810741010.1016/j.phrs.2024.107410 39276955
     [Google Scholar]
  16. MishraM.K. KukalS. PaulP.R. Insights into structural modifications of valproic acid and their pharmacological profile.Molecules202127110410.3390/molecules27010104 35011339
     [Google Scholar]
  17. SafdarA. IsmailF. A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid.Saudi Pharm. J.202331226527810.1016/j.jsps.2022.12.001 36942277
     [Google Scholar]
  18. CsokaA.B. El KouhenN. BennaniS. GetachewB. AschnerM. TizabiY. Roles of epigenetics and glial cells in drug-induced autism spectrum disorder.Biomolecules202414443710.3390/biom14040437 38672454
     [Google Scholar]
  19. ChenO. TahmazianI. FerraraH.J. HuB. ChomiakT. The early overgrowth theory of autism spectrum disorder: Insight into convergent mechanisms from valproic acid exposure and translational models.Prog. Mol. Biol. Transl. Sci.202017327530010.1016/bs.pmbts.2020.04.014 32711813
     [Google Scholar]
  20. Bambini-JuniorV. BaronioD. MacKenzieJ. ZanattaG. RiesgoR dos S. GottfriedC. Prenatal exposure to valproate in animals and autism.In: Comprehensive guide to autism.New YorkSpringer20141779179310.1007/978‑1‑4614‑4788‑7_108
     [Google Scholar]
  21. Bambini-JuniorV. RodriguesL. BehrG.A. MoreiraJ.C.F. RiesgoR. GottfriedC. Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters.Brain Res.2011140881610.1016/j.brainres.2011.06.015 21767826
     [Google Scholar]
  22. TalebA. LinW. XuX. Emerging mechanisms of valproic acid-induced neurotoxic events in autism and its implications for pharmacological treatment.Biomed. Pharmacother.202113711132210.1016/j.biopha.2021.111322 33761592
     [Google Scholar]
  23. Zarate-LopezD. Torres-ChávezA.L. Gálvez-ContrerasA.Y. Gonzalez-PerezO. Three decades of valproate: A current model for studying autism spectrum disorder.Curr. Neuropharmacol.202422226028910.2174/1570159X22666231003121513 37873949
     [Google Scholar]
  24. ChalihaD. AlbrechtM. VaccarezzaM. A systematic review of the valproic-acid-induced rodent model of autism.Dev. Neurosci.2020421124810.1159/000509109 32810856
     [Google Scholar]
  25. ZhaoH. WangQ. YanT. Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates.Transl. Psychiatry20199126710.1038/s41398‑019‑0608‑1 31636273
     [Google Scholar]
  26. ChandaS. AngC.E. LeeQ.Y. Direct reprogramming of human neurons identifies MARCKSL1 as a pathogenic mediator of valproic acid-induced teratogenicity.Cell Stem Cell2019251103119.e610.1016/j.stem.2019.04.021 31155484
     [Google Scholar]
  27. PastorinoP. PrearoM. BarcelóD. Ethical principles and scientific advancements: In vitro, in silico, and non-vertebrate animal approaches for a green ecotoxicology.Green Anal Chem2024810009610009610.1016/j.greeac.2024.100096
     [Google Scholar]
  28. AndersenM.L. WinterL.M.F. Animal models in biological and biomedical research - Experimental and ethical concerns.An. Acad. Bras. Cienc.2019911e2017023810.1590/0001‑3765201720170238
     [Google Scholar]
  29. GordonA. GeschwindD.H. Human in vitro models for understanding mechanisms of autism spectrum disorder.Mol. Autism20201112610.1186/s13229‑020‑00332‑7 32299488
     [Google Scholar]
  30. BerendsenS. FrijlinkE. KroonenJ. Effects of valproic acid on histone deacetylase inhibition in vitro and in glioblastoma patient samples.Neurooncol. Adv.201911vdz02510.1093/noajnl/vdz025 32642660
     [Google Scholar]
  31. DorseyS.G. MocciE. LaneM.V. KruegerB.K. Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism.Transl. Psychiatry202414148210.1038/s41398‑024‑03179‑1 39632793
     [Google Scholar]
  32. HohmannS.S. IlievaM. MichelT.M. In vitro models for asd-patient- derived ipscs and cerebral organoids.In: Progress in molecular biology and translational science.Cambridge, MassachusettsAcademic Press2020Vol. 17335537510.1016/bs.pmbts.2020.04.019
     [Google Scholar]
  33. Khoram-AbadiK.M. BasiriM. NematiM. NozariM. Agmatine ameliorates valproic acid‐induced depletion of parvalbumin‐positive neuron.Int. J. Dev. Neurosci.202484213414210.1002/jdn.10314 38304999
     [Google Scholar]
  34. ZhuM.M. LiH.L. ShiL.H. ChenX.P. LuoJ. ZhangZ.L. The pharmacogenomics of valproic acid.J. Hum. Genet.201762121009101410.1038/jhg.2017.91 28878340
     [Google Scholar]
  35. ChatterjeeD. MaparuK. SinghS. Exploring pathological targets and advancing pharmacotherapy in autism spectrum disorder: Contributions of glial cells and heavy metals.Histol. Histopathol.202531887010.14670/HH‑18‑870 39817414
     [Google Scholar]
  36. QianX. SongH. MingG. Brain organoids: Advances, applications and challenges.Development20191468dev16607410.1242/dev.166074 30992274
     [Google Scholar]
  37. LuoD. XuJ. LiuF. GuZ. Advances and challenges in cerebral organoids research.Adv. NanoBiomed Res.202445230012610.1002/anbr.202300126
     [Google Scholar]
  38. NieL. IrwinC. GeahchanS. SinghK.K. Human pluripotent stem cell (hPSC)-derived models for autism spectrum disorder drug discovery.Expert Opin. Drug Discov.202520223325110.1080/17460441.2024.2416484 39718245
     [Google Scholar]
  39. Sabogal-GuaquetaA.M. Mitchell-GarciaT. HunnemanJ. Brain organoid models for studying the function of iPSC-derived microglia in neurodegeneration and brain tumours.Neurobiol. Dis.202420310674210.1016/j.nbd.2024.106742 39581553
     [Google Scholar]
  40. KowalskiT.W. LordV.O. SgarioniE. Transcriptome meta-analysis of valproic acid exposure in human embryonic stem cells.Eur. Neuropsychopharmacol.202260768810.1016/j.euroneuro.2022.04.008 35635998
     [Google Scholar]
  41. JangE.H. LeeJ.H. KimS.A. Acute valproate exposure induces mitochondrial biogenesis and autophagy with Foxo3a modulation in SH‐SY5Y Cells.Cells20211010252210.3390/cells10102522 34685502
     [Google Scholar]
  42. PageM.J. McKenzieJ.E. BossuytP.M. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.BMJ2021372n7110.1136/bmj.n71 33782057
     [Google Scholar]
  43. LiberatiA. AltmanD.G. TetzlaffJ. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration.PLoS Med.200967e100010010.1371/journal.pmed.1000100 19621070
     [Google Scholar]
  44. MehraS. AhsanA.U. SharmaM. BudhwarM. ChopraM. Gestational Fisetin Exerts neuroprotection by regulating mitochondria-directed canonical Wnt signaling, BBB integrity, and apoptosis in prenatal VPA-induced rodent model of autism.Mol. Neurobiol.20246174001402010.1007/s12035‑023‑03826‑6 38048031
     [Google Scholar]
  45. FarbinM. HejaziA. FakhraeiN. AziziY. MehrabiS. HajisoltaniR. Neuroprotective effects of Apigenin on prenatal Valproic acid-induced autism spectrum disorder in rats.IBRO Neuroscience Reports20241749350210.1016/j.ibneur.2024.10.003 39720795
     [Google Scholar]
  46. LuX.Y. LiM.Q. LiY.T. Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder.Neuropharmacology202425811008910.1016/j.neuropharm.2024.110089 39033904
     [Google Scholar]
  47. CamposJ.M.B. de Aguiar da CostaM. de RezendeV.L. Animal model of autism induced by valproic acid combined with maternal deprivation: Sex-specific effects on inflammation and oxidative stress.Mol. Neurobiol.20256233653367210.1007/s12035‑024‑04491‑z 39316355
     [Google Scholar]
  48. BahorZ. LiaoJ. CurrieG. Development and uptake of an online systematic review platform: The early years of the CAMARADES Systematic Review Facility (SyRF).BMJ Open Science202151e10010310.1136/bmjos‑2020‑100103 35047698
     [Google Scholar]
  49. KaushikG XiaY YangL ThomasMA Psychoactive pharmaceuticals at environmental concentrations induce in vitro gene expression associated with neurological disorders.BMC Genomics201617S3: 435.(Suppl. 3)10.1186/s12864‑016‑2784‑127356971
     [Google Scholar]
  50. PeltierM.R. BehbodikhahJ. RennaH.A. Cholesterol deficiency as a mechanism for autism: A valproic acid model.J. Investig. Med.2024721808710.1177/10815589231210521 37864505
     [Google Scholar]
  51. ZhangY.H. WangT. LiY.F. DengY.N. HeX.L. WangL.J. N-acetylcysteine improves autism-like behavior by recovering autophagic deficiency and decreasing Notch-1/Hes-1 pathway activity.Exp. Biol. Med.20232481196697810.1177/15353702231179924 37377100
     [Google Scholar]
  52. KumamaruE. EgashiraY. TakenakaR. TakamoriS. Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons.Neurosci. Lett.201456914214710.1016/j.neulet.2014.03.066 24708928
     [Google Scholar]
  53. TakedaK. WatanabeT. OyabuK. Valproic acid-exposed astrocytes impair inhibitory synapse formation and function.Sci. Rep.20211112310.1038/s41598‑020‑79520‑7 33420078
     [Google Scholar]
  54. ZhangY. YangC. YuanG. WangZ. CuiW. LiR. Sulindac attenuates valproic acid-induced oxidative stress levels in primary cultured cortical neurons and ameliorates repetitive/stereotypic-like movement disorders in Wistar rats prenatally exposed to valproic acid.Int. J. Mol. Med.201535126327010.3892/ijmm.2014.1996 25384498
     [Google Scholar]
  55. KoH.M. JinY. ParkH.H. Dual mechanisms for the regulation of brain-derived neurotrophic factor by valproic acid in neural progenitor cells.Korean J. Physiol. Pharmacol.201822667968810.4196/kjpp.2018.22.6.679 30402028
     [Google Scholar]
  56. Al-RubaiA. WigmoreP. PrattenM.K. Evaluation of a human neural stem cell culture method for prediction of the neurotoxicity of anti-epileptics.Altern. Lab. Anim.2017452678110.1177/026119291704500202 28598192
     [Google Scholar]
  57. NissenM. BuehlerS.M. StubbeM. GimsaJ. Neuronal in vitro activity is more sensitive to valproate than intracellular ATP: Considerations on conversion problems of IC50 in vitro data for animal replacement.Biosystems2016144354510.1016/j.biosystems.2016.04.009 27091084
     [Google Scholar]
  58. QiC. ZhangJ. WangY. LinM. GaoJ. LuH. Valproic acid enhances neurosphere formation in cultured rat embryonic cortical cells through TGFβ1 signaling.J Biomed Res202236212714010.7555/JBR.36.20210109 35387900
     [Google Scholar]
  59. BattinoD. TomsonT. BonizzoniE. Risk of major congenital malformations and exposure to antiseizure medication monotherapy.JAMA Neurol.202481548148910.1001/jamaneurol.2024.0258 38497990
     [Google Scholar]
  60. OrnoyA. EchefuB. BeckerM. Valproic acid in pregnancy revisited: Neurobehavioral, biochemical and molecular changes affecting the embryo and fetus in humans and in animals: A narrative review.Int. J. Mol. Sci.202325139010.3390/ijms25010390 38203562
     [Google Scholar]
  61. BjørkM.H. ZoegaH. LeinonenM.K. Association of prenatal exposure to antiseizure medication with risk of autism and intellectual disability.JAMA Neurol.202279767268110.1001/jamaneurol.2022.1269 35639399
     [Google Scholar]
  62. GionaF. PaganoJ. VerpelliC. SalaC. Another step toward understanding brain functional connectivity alterations in autism.J. Neurochem.20211591121410.1111/jnc.15452 34252196
     [Google Scholar]
  63. DeCoteauW.E. FoxA.E. Timing and intertemporal choice behavior in the valproic acid rat model of autism spectrum disorder.J. Autism Dev. Disord.20225262414242910.1007/s10803‑021‑05129‑y 34115327
     [Google Scholar]
  64. SmolinskiN.E. SarayaniA. ThaiT.N. JuglS. EwigC.L.Y. WintersteinA.G. Prenatal exposure to valproic acid across various indications for use.JAMA Netw. Open202475e241268010.1001/jamanetworkopen.2024.12680 38776082
     [Google Scholar]
  65. LiaoC. Moyses-OliveiraM. De EschC.E.F. Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies.Cell Genomics20233410027710.1016/j.xgen.2023.100277 37082147
     [Google Scholar]
  66. IlievaM. Fex SvenningsenÅ. ThorsenM. MichelT.M. Psychiatry in a dish: Stem cells and brain organoids modeling autism spectrum disorders.Biol. Psychiatry201883755856810.1016/j.biopsych.2017.11.011 29295738
     [Google Scholar]
  67. MehraS. Ul AhsanA. SethE. ChopraM. Critical Evaluation of valproic acid-induced rodent models of autism: Current and future perspectives.J. Mol. Neurosci.20227261259127310.1007/s12031‑022‑02033‑7 35635674
     [Google Scholar]
  68. OrnoyA. Weinstein-FudimL. BeckerM. SAMe, choline, and valproic acid as possible epigenetic drugs: Their effects in pregnancy with a special emphasis on animal studies.Pharmaceuticals202215219210.3390/ph15020192 35215304
     [Google Scholar]
  69. FardY.A. SadeghiE.N. PajooheshZ. Epigenetic underpinnings of the autistic mind: Histone modifications and prefrontal excitation/inhibition imbalance.Am. J. Med. Genet. B. Neuropsychiatr. Genet.20241958e3298610.1002/ajmg.b.32986 38837296
     [Google Scholar]
  70. MasiniE. LoiE. Vega-BenedettiA.F. An overview of the main genetic, epigenetic and environmental factors involved in autism spectrum disorder focusing on synaptic activity.Int. J. Mol. Sci.20202121829010.3390/ijms21218290 33167418
     [Google Scholar]
  71. MabungaD.F.N. GonzalesE.L.T. KimJ. KimK.C. ShinC.Y. Exploring the validity of valproic acid animal model of autism.Exp. Neurobiol.201524428530010.5607/en.2015.24.4.285 26713077
     [Google Scholar]
  72. MengQ. ZhangW. WangX. Human forebrain organoids reveal connections between valproic acid exposure and autism risk.Transl. Psychiatry202212113010.1038/s41398‑022‑01898‑x 35351869
     [Google Scholar]
  73. ChanW.K. GriffithsR. PriceD.J. MasonJ.O. Cerebral organoids as tools to identify the developmental roots of autism.Mol. Autism20201115810.1186/s13229‑020‑00360‑3 32660622
     [Google Scholar]
  74. RabelingA. GoolamM. Cerebral organoids as an in vitro model to study autism spectrum disorders.Gene Ther.202330965966910.1038/s41434‑022‑00356‑z 35790793
     [Google Scholar]
  75. ChefferA. FlitschL.J. KrutenkoT. Human stem cell-based models for studying autism spectrum disorder-related neuronal dysfunction.Mol. Autism20201119910.1186/s13229‑020‑00383‑w 33308283
     [Google Scholar]
  76. FryeR.E. Mitochondrial dysfunction in autism spectrum disorder: Unique abnormalities and targeted treatments.Semin. Pediatr. Neurol.20203510082910.1016/j.spen.2020.100829 32892956
     [Google Scholar]
  77. UsuiN. KobayashiH. ShimadaS. Neuroinflammation and oxidative stress in the pathogenesis of autism spectrum disorder.Int. J. Mol. Sci.2023246548710.3390/ijms24065487 36982559
     [Google Scholar]
  78. KwonH.S. KohS.H. Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes.Transl. Neurodegener.2020914210.1186/s40035‑020‑00221‑2 33239064
     [Google Scholar]
  79. JuS. XuC. WangG. ZhangL. VEGF-C induces alternative activation of microglia to promote recovery from traumatic brain injury.J. Alzheimers Dis.20196841687169710.3233/JAD‑190063 30958378
     [Google Scholar]
  80. LiuX. LinJ. ZhangH. Oxidative stress in autism spectrum disorder - Current progress of mechanisms and biomarkers.Front. Psychiatry20221381330410.3389/fpsyt.2022.813304 35299821
     [Google Scholar]
  81. TekulaM.R. SunandK. BegumN. KakalijR.M. BakshiV. Neuroprotective effect of resveratrol on valproic acid induced oxidative stress autism in swiss albino mice.Int. J. Pharm. Sci. Drug Res.20181010311010.25004/IJPSDR.2018.100301
     [Google Scholar]
  82. YangJ.Q. YangC.H. YinB.Q. Combined the GABA-A and GABA-B receptor agonists attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.Behav. Brain Res.202140311309410.1016/j.bbr.2020.113094 33359845
     [Google Scholar]
  83. DiJ. LiJ. O’HaraB. The role of GABAergic neural circuits in the pathogenesis of autism spectrum disorder.Int. J. Dev. Neurosci.2020802738510.1002/jdn.10005 31910289
     [Google Scholar]
  84. PutsN.A.J. WodkaE.L. HarrisA.D. Reduced GABA and altered somatosensory function in children with autism spectrum disorder.Autism Res.201710460861910.1002/aur.1691 27611990
     [Google Scholar]
  85. TakumiT. TamadaK. HatanakaF. NakaiN. BoltonP.F. Behavioral neuroscience of autism.Neurosci. Biobehav. Rev.2020110607610.1016/j.neubiorev.2019.04.012 31059731
     [Google Scholar]
  86. HanV.X. PatelS. JonesH.F. DaleR.C. Maternal immune activation and neuroinflammation in human neurodevelopmental disorders.Nat. Rev. Neurol.202117956457910.1038/s41582‑021‑00530‑8 34341569
     [Google Scholar]
  87. PhielC.J. ZhangF. HuangE.Y. GuentherM.G. LazarM.A. KleinP.S. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.J. Biol. Chem.200127639367343674110.1074/jbc.M101287200 11473107
     [Google Scholar]
  88. KimJ. ParkS-H. SunW. The differential developmental neurotoxicity of valproic acid on anterior and posterior neural induction of human pluripotent stem cells.Int. J. Stem Cells2024181495810.15283/ijsc24066 38973150
     [Google Scholar]
  89. HayashiY. OhnumaK. FurueM.K. Pluripotent stem cell heterogeneity.Adv. Exp. Med. Biol.20191123719410.1007/978‑3‑030‑11096‑3_6 31016596
     [Google Scholar]
  90. HorderJ. PetrinovicM.M. MendezM.A. Glutamate and GABA in autism spectrum disorder—A translational magnetic resonance spectroscopy study in man and rodent models.Transl. Psychiatry20188110610.1038/s41398‑018‑0155‑1 29802263
     [Google Scholar]
  91. WangX. ZhaoZ. GuoJ. GABAB1 receptor knockdown in prefrontal cortex induces behavioral aberrations associated with autism spectrum disorder in mice.Brain Res. Bull.202320211075510.1016/j.brainresbull.2023.110755 37678443
     [Google Scholar]
  92. TungE.W.Y. WinnL.M. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: A role for oxidative stress in valproic acid-induced neural tube defects.Mol. Pharmacol.201180697998710.1124/mol.111.072314 21868484
     [Google Scholar]
  93. IshidaK. TatsumiK. MinamigawaY. Neuronal differentiation reporter mice as a new methodology for detecting in vivo developmental neurotoxicity.Biochem. Pharmacol.202220611533210.1016/j.bcp.2022.115332 36323391
     [Google Scholar]
  94. JuliandiB. TanemuraK. IgarashiK. Reduced adult hippocampal neurogenesis and cognitive impairments following prenatal treatment of the antiepileptic drug valproic acid.Stem Cell Reports201556996100910.1016/j.stemcr.2015.10.012 26677766
     [Google Scholar]
  95. WillingerY. Friedland CohenD.R. TurgemanG. Exogenous IL-17A alleviates social behavior deficits and increases neurogenesis in a murine model of autism spectrum disorders.Int. J. Mol. Sci.202325143210.3390/ijms25010432 38203599
     [Google Scholar]
  96. AlmeidaL.E.F. RobyC.D. KruegerB.K. Increased BDNF expression in fetal brain in the valproic acid model of autism.Mol. Cell. Neurosci.201459576210.1016/j.mcn.2014.01.007 24480134
     [Google Scholar]
  97. CamusoS. La RosaP. FiorenzaM.T. CanteriniS. Pleiotropic effects of BDNF on the cerebellum and hippocampus: Implications for neurodevelopmental disorders.Neurobiol. Dis.202216310560610.1016/j.nbd.2021.105606 34974125
     [Google Scholar]
  98. JiangS. XiaoL. SunY. The GABAB receptor agonist STX209 reverses the autism like behaviour in an animal model of autism induced by prenatal exposure to valproic acid.Mol. Med. Rep.202225515410.3892/mmr.2022.12670 35244195
     [Google Scholar]
  99. Guimarães-SouzaE.M. JoselevitchC. BrittoL.R.G. ChiavegattoS. Retinal alterations in a pre-clinical model of an autism spectrum disorder.Mol. Autism20191011910.1186/s13229‑019‑0270‑8 31011411
     [Google Scholar]
  100. QinL. DaiX. YinY. Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.Mol. Cell. Neurosci.201675273510.1016/j.mcn.2016.06.004 27343825
     [Google Scholar]
  101. GoH.S. KimK.C. ChoiC.S. Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3β/β-catenin pathway.Neuropharmacology20126361028104110.1016/j.neuropharm.2012.07.028 22841957
     [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273374315250417094713
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Valproate Exposure as an In vitro Model for Studying Morpho-Molecular Features of ASD: A Systematic Review
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 24, 766 (2025); https://doi.org/10.2174/0118715273374315250417094713
/content/journals/cnsnddt/10.2174/0118715273374315250417094713
/content/journals/cnsnddt/10.2174/0118715273374315250417094713
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  • Article Type:     Review Article
Keyword(s): autism spectrum disorder; in vitro; morpho-molecular alterations; neuronal cell culture; neurotoxicity; Valproic acid

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