The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats.

Prenatal exposure to valproic acid (VPA) induces neural tube defects and impairment in social behaviors related to autistic spectrum disorder in newborns, which make it a useful animal model of autism. In this study, we compared the effects of different time window of prenatal valproic acid exposure for inducing the altered social behaviors relevant to autism from embryonic day 7 to embryonic day 15 in Sprague-Dawley rats to determine the critical periods for the impairment. Compared to E7, E9.5 and E15 exposure, VPA exposure at E12 showed most significant changes in behaviors over control animals with reduced sociability and social preference. E9.5 exposure to valproic acid showed strong reproductive toxicity including decrease in the number of live birth. In general, exposure at E15 showed only marginal effects on reproduction and social behaviors. Finally, VPA-exposed rats at E12 were more sensitive to electric shock than VPA-exposed rats at any other periods. These results suggested that E12 is the critical period in rats when valproate exposure has prominent effects for inducing the altered social behavior similar to human autistic behavior.

[1]  D. Lindhout,et al.  IN-UTERO EXPOSURE TO VALPROATE AND NEURAL TUBE DEFECTS , 1986, The Lancet.

[2]  L. Kanner.  Autistic disturbances of affective contact. , 1968, Acta paedopsychiatrica.

[3]  H. Nau,et al.  Diurnal variation of folate concentrations in mouse embryo and plasma: the protective effect of folinic acid on valproic-acid-induced teratogenicity is time dependent. , 1991, Reproductive toxicology.

[4]  R. Kavlock,et al.  Developmental toxicity and structure-activity relationships of aliphatic acids, including dose-response assessment of valproic acid in mice and rats. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[5]  D. Buxhoeveden,et al.  Disruption in the Inhibitory Architecture of the Cell Minicolumn: Implications for Autisim , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[6]  Yoshio Imura,et al.  Nonexploratory movement and behavioral alterations in a thalidomide or valproic acid-induced autism model rat , 2010, Neuroscience Research.

[7]  A. Obenaus,et al.  Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[9]  P. Turnpenny,et al.  A clinical study of 57 children with fetal anticonvulsant syndromes , 2000 .

[10]  Henry Markram,et al.  Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid , 2007, Proceedings of the National Academy of Sciences.

[11]  W. Briner,et al.  Arnold-Chiari-like malformation associated with a valproate model of spina bifida in the rat. , 1995, Teratology.

[12]  J. Ramsdell,et al.  Maternal–Fetal Transfer of Domoic Acid in Rats at Two Gestational Time Points , 2007, Environmental health perspectives.

[13]  P. Morselli,et al.  Alterations of GABA-mediated synaptic transmission in human epilepsy. , 1984, Advances in neurology.

[14]  J. Lacaille,et al.  Selective loss of GABA neurons in area CA1 of the rat hippocampus after intraventricular kainate , 1998, Epilepsy Research.

[15]  Broadhurst Ad.  L-tryptophan verses E.C.T. , 1970 .

[16]  H. Nau,et al.  Valproic acid-induced spina bifida: a mouse model. , 1992, Teratology.

[17]  D. Guilloteau,et al.  Behavior and serotonergic disorders in rats exposed prenatally to valproate: A model for autism , 2010, Neuroscience Letters.

[18]  S. Schulz,et al.  Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices , 2002, Biological Psychiatry.

[19]  Y. Ben-Ari,et al.  Dendritic but not somatic GABAergic inhibition is decreased in experimental epilepsy , 2001, Nature Neuroscience.

[20]  F. Wilcoxon,et al.  A simplified method of evaluating dose-effect experiments. , 1948, The Journal of pharmacology and experimental therapeutics.

[21]  A. Jongen-Rêlo,et al.  Highly Specific Neuron Loss Preserves Lateral Inhibitory Circuits in the Dentate Gyrus of Kainate-Induced Epileptic Rats , 1999, The Journal of Neuroscience.

[22]  A. Czeizel,et al.  VALPROIC ACID AND SPINA BIFIDA , 1982, The Lancet.

[23]  P. Rodier,et al.  The teratology of autism , 2005, International Journal of Developmental Neuroscience.

[24]  J. R. Hughes,et al.  EEG and Seizures in Autistic Children and Adolescents: Further Findings with Therapeutic Implications , 2005, Clinical EEG and neuroscience.

[25]  H. Markram,et al.  Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism , 2008, Neuropsychopharmacology.

[26]  H. Nau,et al.  Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis. , 1992, Neurology.

[27]  Evans Da.  Letter: Coeliac disease and HL-A8. , 1973 .

[28]  A. Ornoy.  The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. , 2003, Toxicology letters.

[29]  I M Smith,et al.  First report of a Canadian epidemiological study of autistic syndromes. , 1988, Journal of child psychology and psychiatry, and allied disciplines.

[30]  H. Nau,et al.  Evaluation of valproic acid (VPA) developmental toxicity and pharmacokinetics in Sprague-Dawley rats. , 1988, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[31]  A. Ornoy.  Valproic acid in pregnancy: how much are we endangering the embryo and fetus? , 2009, Reproductive toxicology.

[32]  C. Vorhees,et al.  Teratogenicity and developmental toxicity of valproic acid in rats. , 1987, Teratology.

[33]  Kevin L. Brown,et al.  Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism , 2007, Behavioural Brain Research.

[34]  M. R. Gomez.  Possible teratogenicity of valproic acid. , 1981, The Journal of pediatrics.

[35]  B. Dalens,et al.  Teratogenicity of valproic acid. , 1980, The Journal of pediatrics.

[36]  H. Markram,et al.  Hyper-Connectivity and Hyper-Plasticity in the Medial Prefrontal Cortex in the Valproic Acid Animal Model of Autism , 2008, Frontiers in neural circuits.

[37]  S. Ceylaner,et al.  A case of fetal anticonvulsant syndrome with severe bilateral upper limb defect , 2006, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[38]  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.

[39]  B. Gasser,et al.  Isolated fetal bilateral radial ray reduction associated with valproic acid usage. , 1994, Fetal diagnosis and therapy.

[40]  T. Kemper,et al.  Density and Distribution of Hippocampal Neurotransmitter Receptors in Autism: An Autoradiographic Study , 2001, Journal of autism and developmental disorders.

[41]  S. Spence,et al.  The Role of Epilepsy and Epileptiform EEGs in Autism Spectrum Disorders , 2009, Pediatric Research.

[42]  A. Ornoy,et al.  The use of psychiatric drugs in pregnancy and lactation. , 2000, The Israel journal of psychiatry and related sciences.

[43]  J. Clayton-Smith,et al.  Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes , 2005, Archives of Disease in Childhood - Fetal and Neonatal Edition.

[44]  C. Houser,et al.  Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures , 1996, Epilepsy Research.

[45]  M. Stanton,et al.  Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism , 2009, Behavioural Brain Research.

[46]  van Gelder Nm,et al.  Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy. , 1986 .

[47]  J. Holson,et al.  Appropriate Exposure Routes and Doses in Studies Designed to Assess Developmental Toxicity: A Case Study of Inorganic Arsenic , 1999 .

[48]  S. Shioda,et al.  Observation of fetal brain in a rat valproate-induced autism model: a developmental neurotoxicity study , 2009, International Journal of Developmental Neuroscience.

[49]  中里 茜.  Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism , 2008 .

[50]  M. Kato,et al.  Increased Monoamine Concentration in the Brain and Blood of Fetal Thalidomide- and Valproic Acid–Exposed Rat: Putative Animal Models for Autism , 2002, Pediatric Research.

[51]  R. Browning,et al.  Electroshock- and pentylenetetrazol-induced seizures in genetically epilepsy-prone rats (GEPRs): differences in threshold and pattern , 1990, Epilepsy Research.

[52]  Alterations of hippocampal GABAergic system contribute to development of spontaneous recurrent seizures in the rat lithium‐pilocarpine model of temporal lobe epilepsy , 2001, Hippocampus.

[53]  H. Son,et al.  Valproic acid promotes neuronal differentiation by induction of proneural factors in association with H4 acetylation , 2009, Neuropharmacology.

[54]  F. Gage,et al.  Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[55]  P. Rodier,et al.  Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. , 2000, Neurotoxicology and teratology.

[56]  R. Przewłocki,et al.  Environmental Enrichment Reverses Behavioral Alterations in Rats Prenatally Exposed to Valproic Acid: Issues for a Therapeutic Approach in Autism , 2006, Neuropsychopharmacology.

[57]  P. Turnpenny,et al.  A clinical study of 57 children with fetal anticonvulsant syndromes , 2000, Journal of medical genetics.

[58]  J. Cheong,et al.  Anticonvulsant effect of wogonin isolated from Scutellaria baicalensis. , 2007, European journal of pharmacology.

[59]  M. Merzenich,et al.  Model of autism: increased ratio of excitation/inhibition in key neural systems , 2003, Genes, brain, and behavior.

[60]  H. Nau.  Valproic acid-induced neural tube defects. , 1994, Ciba Foundation symposium.

[61]  T. Freund,et al.  Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine‐induced seizures , 2003, The Journal of comparative neurology.

[62]  S. Schneider.  Valproic acid , 1980, The Western journal of medicine.

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

[64]  J. Crawley.  Designing mouse behavioral tasks relevant to autistic-like behaviors. , 2004, Mental retardation and developmental disabilities research reviews.

[65]  Joseph Altman,et al.  Atlas of prenatal rat brain development , 1994 .

[66]  A. Ornoy.  Neuroteratogens in man: an overview with special emphasis on the teratogenicity of antiepileptic drugs in pregnancy. , 2006, Reproductive toxicology.

[67]  J. Altman,et al.  Development of the brain stem in the rat. I. Thymidine‐radiographic study of the time of origin of neurons of the lower medulla , 1980, The Journal of comparative neurology.

[68]  P. Rodier,et al.  Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei , 1996, The Journal of comparative neurology.

[69]  J. Kromberg,et al.  Fetal Valproate Syndrome: Clinical and Neuro‐developmental Features in Two Sibling Pairs , 1994 .

[70]  M. Narita,et al.  Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism , 2005, International Journal of Developmental Neuroscience.

[71]  I. Takasaki,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 , 2009, Neuroscience Research.

[72]  Y. Nakatani,et al.  Swim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism , 2008, Brain Research.

[73]  B. Doble,et al.  GSK-3 is a master regulator of neural progenitor homeostasis , 2009, Nature Neuroscience.

[74]  A. Gieryk,et al.  Prenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism , 2007, Psychopharmacology.

[75]  A. Sherwin,et al.  Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy. , 1986, Advances in neurology.

[76]  Y. Nakatani,et al.  Abnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism , 2007, Neuroscience Research.