Transcriptional and splicing dysregulation in the prefrontal cortex in valproic acid rat model of autism.

Gene-environmental interaction could be the major cause of autism. The aim of the current study is to detect the effects of valproic acid on gene expression profiles and alternatively spliced genes in the prefrontal cortex in rat models of autism. Female rats received a single intraperitoneal injection of 600 mg/kg valproic acid at day 12.5 post-conception, and controls were injected with saline. Only male offspring were employed in the current study. RNA sequencing was used to investigate transcriptome in the prefrontal cortex of VPA-exposed rats. There were 3228 differently expressed genes and 637 alternative spliced genes, in VPA rats compared to controls. Pathways enrichment among the differently expressed genes and alternatively spliced genes were associated with neurological diseases and neural system development. The results implied VPA affected transcriptional and splicing events genome-wide and the transcriptional and splicing events may be associated with the autistic behaviors of VPA rats.

[1]  Matthew D. Young,et al.  Gene ontology analysis for RNA-seq: accounting for selection bias , 2010, Genome Biology.

[2]  T. Kubota,et al.  Environmental Research and Public Health Epigenetic Effect of Environmental Factors on Autism Spectrum Disorders , 2022 .

[3]  D. Guilloteau,et al.  Fetal exposure to teratogens: Evidence of genes involved in autism , 2011, Neuroscience & Biobehavioral Reviews.

[4]  J. Hutsler,et al.  Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders , 2010, Brain Research.

[5]  D. Amaral,et al.  Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders , 2013, Molecular Autism.

[6]  C. Gottfried,et al.  Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters , 2011, Brain Research.

[7]  Michael E. Greenberg,et al.  Activity-dependent neuronal signalling and autism spectrum disorder , 2013, Nature.

[8]  N. Rezaei,et al.  Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis , 2017, Journal of Autism and Developmental Disorders.

[9]  Y. Egashira,et al.  Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons , 2014, Neuroscience Letters.

[10]  D. Geschwind,et al.  Autism spectrum disorders: developmental disconnection syndromes , 2007, Current Opinion in Neurobiology.

[11]  J. Pennings,et al.  Comparison of gene expression regulation in mouse- and human embryonic stem cell assays during neural differentiation and in response to valproic acid exposure. , 2015, Reproductive toxicology.

[12]  H. Markram,et al.  General developmental health in the VPA-rat model of autism , 2013, Front. Behav. Neurosci..

[13]  B. K. Krueger,et al.  Increased BDNF expression in fetal brain in the valproic acid model of autism , 2014, Molecular and Cellular Neuroscience.

[14]  B. Shin,et al.  Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression. , 2013, Endocrinology.

[15]  Hisao Nishijo,et al.  Demethylation of Specific Wnt/β‐Catenin Pathway Genes and its Upregulation in Rat Brain Induced by Prenatal Valproate Exposure , 2010, Anatomical record.

[16]  H. Markram,et al.  Hyperconnectivity of Local Neocortical Microcircuitry Induced by Prenatal Exposure to Valproic Acid , 2007 .

[17]  E. L. Gonzales,et al.  Exploring the Validity of Valproic Acid Animal Model of Autism , 2015, Experimental neurobiology.

[18]  Stephen J. Guter,et al.  Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders , 2014, American journal of human genetics.

[19]  T. Chomiak,et al.  Alterations of neocortical development and maturation in autism: insight from valproic acid exposure and animal models of autism. , 2013, Neurotoxicology and teratology.

[20]  F. Zhang,et al.  Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2 , 2016, Nature.

[21]  D. deCatanzaro,et al.  Behavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid , 2010, Neuroscience.

[22]  Chang Soon Choi,et al.  Male‐specific alteration in excitatory post‐synaptic development and social interaction in pre‐natal valproic acid exposure model of autism spectrum disorder , 2013, Journal of neurochemistry.

[23]  Chang Soon Choi,et al.  Translational Regulation of NeuroD1 Expression by FMRP: Involvement in Glutamatergic Neuronal Differentiation of Cultured Rat Primary Neural Progenitor Cells , 2013, Cellular and Molecular Neurobiology.

[24]  P. Penzes,et al.  Dendritic spine pathology in neuropsychiatric disorders , 2011, Nature Neuroscience.

[25]  Ryszard Przewłocki,et al.  Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Animal Model of Autism , 2005, Neuropsychopharmacology.

[26]  Daniel H. Geschwind,et al.  Genetics of autism spectrum disorders , 2011, Trends in Cognitive Sciences.

[27]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[28]  J. Bischofberger,et al.  Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure , 2016, Scientific Reports.

[29]  S. Scherer,et al.  Autism spectrum disorder in the genetics clinic: a review , 2013, Clinical genetics.

[30]  Z. Talebizadeh,et al.  A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines , 2014, Psychiatric genetics.

[31]  Chang Soon Choi,et al.  MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism , 2014, Molecular Neurobiology.

[32]  E. Courchesne,et al.  Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection , 2005, Current Opinion in Neurobiology.

[33]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[34]  B. Williams,et al.  Mapping and quantifying mammalian transcriptomes by RNA-Seq , 2008, Nature Methods.

[35]  Christian von Mering,et al.  STRING: a database of predicted functional associations between proteins , 2003, Nucleic Acids Res..

[36]  Tao Cai,et al.  Automated genome annotation and pathway identification using the KEGG Orthology (KO) as a controlled vocabulary , 2005, Bioinform..

[37]  M. Phillips,et al.  Dendritic spine dysgenesis in autism related disorders , 2015, Neuroscience Letters.

[38]  Eric C. Griffith,et al.  Derepression of BDNF Transcription Involves Calcium-Dependent Phosphorylation of MeCP2 , 2003, Science.

[39]  Yuta Hara,et al.  Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. , 2013, The international journal of neuropsychopharmacology.

[40]  R. Przewłocki,et al.  Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid , 2008, Psychoneuroendocrinology.

[41]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[42]  Se Jin Jeon,et al.  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 , 2012, Neuropharmacology.

[43]  Stephen J. Glatt,et al.  Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats , 2013, International Journal of Developmental Neuroscience.

[44]  T. Matsuda,et al.  Effect of prenatal valproic acid exposure on cortical morphology in female mice. , 2012, Journal of pharmacological sciences.

[45]  Bradley S. Peterson,et al.  Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits , 2014, Neuron.

[46]  Thomas Bourgeron,et al.  A synaptic trek to autism , 2009, Current Opinion in Neurobiology.

[47]  Guang Chen,et al.  Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis , 2004, The Journal of Neuroscience.

[48]  D. Amaral,et al.  Neuroanatomy of autism , 2008, Trends in Neurosciences.

[49]  S. Horvath,et al.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology , 2011, Nature.

[50]  Joshua F. Robinson,et al.  Valproic acid-induced gene expression responses in rat whole embryo culture and comparison across in vitro developmental and non-developmental models. , 2013, Reproductive toxicology.

[51]  Kwang Ho Ko,et al.  The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. , 2011, Toxicology letters.

[52]  F. Sharp,et al.  Differences in exon expression and alternatively spliced genes in blood of multiple sclerosis compared to healthy control subjects , 2011, Journal of Neuroimmunology.

[53]  Jordan Grafman,et al.  The medial prefrontal cortex mediates social event knowledge , 2009, Trends in Cognitive Sciences.