丙戊酸(valproic acid；VPA)是現今一種廣泛用於治療癲癇與精神疾病的臨床用藥，但是在一些臨床的證據卻顯示在一些患有癲癇的孕婦在服用VPA之後，其體內胎兒出生後會有認知缺陷、社交障礙和焦慮行為等類自閉症行為。然而，在出生後胎兒也可能會因為外在的環境因子造成發育時期的基因表現受到不正常的調控，造成後天神經發育行為的偏差。現今，造成神經行為異常機制到目前還不清楚。因此本篇的研究目的是利用出生後七天公鼠(P7)腹腔注射VPA誘導產生焦慮行為。探討其在不同時期，VPA對大腦發育的影響機制與行為。西方點墨法分析海馬迴區H3K9乙醯化情形，發現腹腔注射VPA增加海馬迴區H3K9乙醯化蛋白量。在高架十字迷宮的結果顯示，二、四、六和八週大老鼠給予腹腔注射VPA處理組相較於控制組具有顯著的焦慮行為。以開放場域測試(open field test)也發現VPA處理的大鼠具有較高的焦慮程度，並且有異常的運動行為。在強迫游泳實驗測試(forced swimming test)，發現VPA處理大鼠在水中不動(immobility)的時間較控制組長，顯示VPA處理組具有較抑鬱的行為。利用免疫組織化學染色實驗觀察海馬迴區BrdU和Ki67的表現的確有顯著性的上升，表示出生後暴露VPA會誘導老鼠細胞增生的情形。除此之外我們也發現VPA會調控海馬迴中分化相關基因分析海馬迴神經分化基因NeuroD和doublecortin (DCX)表現，發現此兩種神經特化的基因在VPA處理組的表現比在控制組降低。VPA 處理24小時之後，olig1與olig2寡突膠細胞的基因表現受到顯著抑制。但是，星狀膠細胞特有的GFAP基因在VPA處理組海馬迴在24小時至四週大量表現。綜合上述結果，出生後暴露丙物酸會誘導海馬迴中的細胞增生並抑制神經分化，並誘發發育時期焦慮和抑鬱的行為。

Valproic acid (VPA) is a widely used medicine to treat or prevent epilepsy and bipolar disorder. However, exposure to valproate during pregnancy causes behavioral impairments, like cognitive delay, social interaction, anxious behaviors and interests which is related to symptoms of autistic spectrum disorder. The molecular mechanism remains largely unknown. In our laboratory, we used the model of male rat pups receiving 200 mg/kg of VPA by intraperitoneal injection (ip) at postnatal day 7 (P7). The results from elevated plus-maze test at 2,4 and 6 weeks post injection showed the VPA-injected rats exhibited impaired social interaction and anxiety. Through the open field test, we found that VPA-treated rats displayed an anxious behavior and abnormal locomotion. From the forced swimming test, The VPA-injected rats increase immobility time and depressive behavior. Given the fact that cortex and hippocampus are associated with autistic behaviors, we examined cellular and molecular alterations in the hippocampus of rat at 24 h, week 2, 4, and6. An increased level of acetylated histone H3 was detected at 24 h in hippocampus of rat pups which receiving VPA injection when compared to vehicle-treated rats. BrdU+ -cells or Ki67+ -cells in the hippocampus of rats were also increased at the four observed time point after VPA exposure. In addition, neuronal differentiation gene NeuroD and neuronal migration protein doublecortin were downregulated in the hippocampus of VPA-treated rats at the four detected time points. Olig1 and Olig2 gene expression was also reduced at 24 h after VPA injection, but GFAP mRNA expression was increased in VPA-treated group. Collectively, a bolus of postnatal VPA exposure induced increased cell proliferation and reduced neural differentiation in developing hippocampus of rats with anxiety and depression.

Abel, E.L., and R.J. Sokol. 1986. Fetal alcohol syndrome is now leading cause of mental retardation. Lancet. 2:1222.
Abel, E.L., and R.J. Sokol. 1987. Incidence of fetal alcohol syndrome and economic impact of FAS-related anomalies. Drug and alcohol dependence. 19:51-70.
Ahlsen, G., L. Rosengren, M. Belfrage, A. Palm, K. Haglid, A. Hamberger, and C. Gillberg. 1993. Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Biological psychiatry. 33:734-743.
Amaral DG, L.P. 2007. Hippocampal neuroanatomy. 37-114 pp.
Amiri, A., W. Cho, J. Zhou, S.G. Birnbaum, C.M. Sinton, R.M. McKay, and L.F. Parada. 2012. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32:5880-5890.
Aylward, E.H., N.J. Minshew, K. Field, B.F. Sparks, and N. Singh. 2002. Effects of age on brain volume and head circumference in autism. Neurology. 59:175-183.
Bachevalier, J., and M. Beauregard. 1993. Maturation of medial temporal lobe memory functions in rodents, monkeys, and humans. Hippocampus. 3 Spec No:191-201.
Bailey, A., P. Luthert, A. Dean, B. Harding, I. Janota, M. Montgomery, M. Rutter, and P. Lantos. 1998. A clinicopathological study of autism. Brain : a journal of neurology. 121 ( Pt 5):889-905.
Bannerman, D.M., J.N.P. Rawlins, S.B. McHugh, R.M.J. Deacon, B.K. Yee, T. Bast, W.N. Zhang, H.H.J. Pothuizen, and J. Feldon. 2004. Regional dissociations within the hippocampus—memory and anxiety. Neuroscience & Biobehavioral Reviews. 28:273-283.
Bartzokis, G., M. Beckson, P.H. Lu, N. Edwards, R. Rapoport, E. Wiseman, and P. Bridge. 2000. Age-related brain volume reductions in amphetamine and cocaine addicts and normal controls: implications for addiction research. Psychiatry research. 98:93-102.
Bauman, M.L., and T.L. Kemper. 2005. Neuroanatomic observations of the brain in autism: a review and future directions. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 23:183-187.
Belzung, C., and G. Griebel. 2001. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behavioural brain research. 125:141-149.
Benes, F.M., and S. Berretta. 2000. Amygdalo-entorhinal inputs to the hippocampal formation in relation to schizophrenia. Annals of the New York Academy of Sciences. 911:293-304.
Blundell, J., C.A. Blaiss, M.R. Etherton, F. Espinosa, K. Tabuchi, C. Walz, M.F. Bolliger, T.C. Sudhof, and C.M. Powell. 2010. Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience. 30:2115-2129.
Bouwknecht, J.A., and R. Paylor. 2002. Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behavioural brain research. 136:489-501.
Boyko, M., A.N. Azab, R. Kuts, B.F. Gruenbaum, S.E. Gruenbaum, I. Melamed, E. Brotfain, Y. Shapira, E. Cesnulis, and A. Zlotnik. 2013. The neuro-behavioral profile in rats after subarachnoid hemorrhage. Brain research. 1491:109-116.
Bruel-Jungerman, E., C. Rampon, and S. Laroche. 2007. Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Reviews in the neurosciences. 18:93-114.
Bug, G., H. Gul, K. Schwarz, H. Pfeifer, M. Kampfmann, X. Zheng, T. Beissert, S. Boehrer, D. Hoelzer, O.G. Ottmann, and M. Ruthardt. 2005. Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells. Cancer research. 65:2537-2541.
Burke, S.N., and C.A. Barnes. 2006. Neural plasticity in the ageing brain. Nature reviews. Neuroscience. 7:30-40.
Caspi, M., R. Atlas, A. Kantor, T. Sapir, and O. Reiner. 2000. Interaction between LIS1 and doublecortin, two lissencephaly gene products. Human molecular genetics. 9:2205-2213.
Chakrabarti, L., T.K. Best, N.P. Cramer, R.S. Carney, J.T. Isaac, Z. Galdzicki, and T.F. Haydar. 2010. Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome. Nature neuroscience. 13:927-934.
Chan, T.J., L.S. Her, H.J. Liaw, M.C. Chen, and S.F. Tzeng. 2012. Retinoic acid mediates the expression of glutamate transporter-1 in rat astrocytes through genomic RXR action and non-genomic protein kinase C signaling pathway. J Neurochem. 121:537-550.
Choe, Y., A. Kozlova, D. Graf, and S.J. Pleasure. 2013. Bone morphogenic protein signaling is a major determinant of dentate development. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33:6766-6775.
Chomiak, T., V. Karnik, E. Block, and B. Hu. 2010. Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism. BMC neuroscience. 11:102.
Clelland, C.D., M. Choi, C. Romberg, G.D. Clemenson, Jr., A. Fragniere, P. Tyers, S. Jessberger, L.M. Saksida, R.A. Barker, F.H. Gage, and T.J. Bussey. 2009. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 325:210-213.
Cook, M.N., R.W. Williams, and L. Flaherty. 2001. Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration. Behavioral neuroscience. 115:468-476.
Courchesne, E., C.M. Karns, H.R. Davis, R. Ziccardi, R.A. Carper, Z.D. Tigue, H.J. Chisum, P. Moses, K. Pierce, C. Lord, A.J. Lincoln, S. Pizzo, L. Schreibman, R.H. Haas, N.A. Akshoomoff, and R.Y. Courchesne. 2001. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology. 57:245-254.
Crawley, J.N., J.K. Belknap, A. Collins, J.C. Crabbe, W. Frankel, N. Henderson, R.J. Hitzemann, S.C. Maxson, L.L. Miner, A.J. Silva, J.M. Wehner, A. Wynshaw-Boris, and R. Paylor. 1997. Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology. 132:107-124.
Critchley, H., E. Daly, M. Phillips, M. Brammer, E. Bullmore, S. Williams, T. Van Amelsvoort, D. Robertson, A. David, and D. Murphy. 2000. Explicit and implicit neural mechanisms for processing of social information from facial expressions: a functional magnetic resonance imaging study. Human brain mapping. 9:93-105.
Dager, S.R., L. Wang, S.D. Friedman, D.W. Shaw, J.N. Constantino, A.A. Artru, G. Dawson, and J.G. Csernansky. 2007. Shape mapping of the hippocampus in young children with autism spectrum disorder. AJNR. American journal of neuroradiology. 28:672-677.
Dakin, S., and U. Frith. 2005. Vagaries of visual perception in autism. Neuron. 48:497-507.
Davis, R., D.H. Peters, and D. McTavish. 1994. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs. 47:332-372.
Dawson, G., S. Webb, G.D. Schellenberg, S. Dager, S. Friedman, E. Aylward, and T. Richards. 2002. Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives. Development and psychopathology. 14:581-611.
Dendrinos, G., M. Hemelt, and A. Keller. 2011. Prenatal VPA Exposure and Changes in Sensory Processing by the Superior Colliculus. Frontiers in integrative neuroscience. 5:68.
Deng, W., J.B. Aimone, and F.H. Gage. 2010. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature reviews. Neuroscience. 11:339-350.
Deth, R., C. Muratore, J. Benzecry, V.A. Power-Charnitsky, and M. Waly. 2008. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology. 29:190-201.
DiLiberti, J.H., P.A. Farndon, N.R. Dennis, and C.J.R. Curry. 1984. The fetal valproate syndrome. American Journal of Medical Genetics. 19:473-481.
Dong, W.K., and W.T. Greenough. 2004. Plasticity of nonneuronal brain tissue: roles in developmental disorders. Mental retardation and developmental disabilities research reviews. 10:85-90.
Du, J., T.K. Creson, L.J. Wu, M. Ren, N.A. Gray, C. Falke, Y. Wei, Y. Wang, R. Blumenthal, R. Machado-Vieira, P. Yuan, G. Chen, M. Zhuo, and H.K. Manji. 2008. The role of hippocampal GluR1 and GluR2 receptors in manic-like behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28:68-79.
Dufour-Rainfray, D., P. Vourc'h, A.M. Le Guisquet, L. Garreau, D. Ternant, S. Bodard, E. Jaumain, Z. Gulhan, C. Belzung, C.R. Andres, S. Chalon, and D. Guilloteau. 2010. Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism. Neuroscience letters. 470:55-59.
Durand, C.M., C. Betancur, T.M. Boeckers, J. Bockmann, P. Chaste, F. Fauchereau, G. Nygren, M. Rastam, I.C. Gillberg, H. Anckarsater, E. Sponheim, H. Goubran-Botros, R. Delorme, N. Chabane, M.C. Mouren-Simeoni, P. de Mas, E. Bieth, B. Roge, D. Heron, L. Burglen, C. Gillberg, M. Leboyer, and T. Bourgeron. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature genetics. 39:25-27.
Engin, E., and D. Treit. 2007. The role of hippocampus in anxiety: intracerebral infusion studies. Behavioural pharmacology. 18:365-374.
Estes, A., D.W. Shaw, B.F. Sparks, S. Friedman, J.N. Giedd, G. Dawson, M. Bryan, and S.R. Dager. 2011. Basal ganglia morphometry and repetitive behavior in young children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 4:212-220.
Farioli-Vecchioli, S., D. Saraulli, M. Costanzi, S. Pacioni, I. Cinà, M. Aceti, L. Micheli, A. Bacci, V. Cestari, and F. Tirone. 2008. The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS biology. 6:e246.
Feng, J., S. Fouse, and G. Fan. 2007. Epigenetic regulation of neural gene expression and neuronal function. Pediatric research. 61:58R-63R.
Foley, A.G., S. Gannon, N. Rombach-Mullan, A. Prendergast, C. Barry, A.W. Cassidy, and C.M. Regan. 2012. Class I histone deacetylase inhibition ameyjo4liorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder. Neuropharmacology. 63:750-760.
Fournier, Neil M., and Ronald S. Duman. 2013. Illuminating Hippocampal Control of Fear Memory and Anxiety. Neuron. 77:803-806.
Fried, I., K.A. Cameron, S. Yashar, R. Fong, and J.W. Morrow. 2002. Inhibitory and excitatory responses of single neurons in the human medial temporal lobe during recognition of faces and objects. Cerebral cortex (New York, N.Y. : 1991). 12:575-584.
Fried, I., K.A. MacDonald, and C.L. Wilson. 1997. Single neuron activity in human hippocampus and amygdala during recognition of faces and objects. Neuron. 18:753-765.
Froescher, W., R. Gugler, M. Niesen, and F. Hoffmann. 1984. Protein Binding of Valproic Acid in Maternal and Umbilical Cord Serum. Epilepsia. 25:244-249.
Gaillard, W.D., T. Zeffiro, S. Fazilat, C. DeCarli, and W.H. Theodore. 1996. Effect of valproate on cerebral metabolism and blood flow: an 18F-2-deoxyglucose and 15O water positron emission tomography study. Epilepsia. 37:515-521.
Gary B. Mesibov, L.W.A., Laura G. Klinger. 1998. Autism: Understanding the Disorder. Plenum Press, New York.
Gean, P.W., C.C. Huang, C.R. Hung, and J.J. Tsai. 1994. Valproic acid suppresses the synaptic response mediated by the NMDA receptors in rat amygdalar slices. Brain research bulletin. 33:333-336.
Gleeson, J.G., K.M. Allen, J.W. Fox, E.D. Lamperti, S. Berkovic, I. Scheffer, E.C. Cooper, W.B. Dobyns, S.R. Minnerath, M.E. Ross, and C.A. Walsh. 1998. doublecortin, a Brain-Specific Gene Mutated in Human X-Linked Lissencephaly and Double Cortex Syndrome, Encodes a Putative Signaling Protein. Cell. 92:63-72.
Go, H.S., K.C. Kim, C.S. Choi, S.J. Jeon, K.J. Kwon, S.-H. Han, J. Lee, J.H. Cheong, J.H. Ryu, C.-H. Kim, K.H. Ko, and C.Y. Shin. 2012. 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. Neuropharmacology. 63:1028-1041.
Gobbi, G., and L. Janiri. 2006. Sodium- and magnesium-valproate in vivo modulate glutamatergic and GABAergic synapses in the medial prefrontal cortex. Psychopharmacology. 185:255-262.
Godin, Y., L. Heiner, J. Mark, and P. Mandel. 1969. Effect of DI-n-propylacetate, an anticonvulsive compound, on GABA metabolism. Journal of Neurochemistry. 16:869-873.
Gottlicher, M., S. Minucci, P. Zhu, O.H. Kramer, A. Schimpf, S. Giavara, J.P. Sleeman, F. Lo Coco, C. Nervi, P.G. Pelicci, and T. Heinzel. 2001. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. The EMBO journal. 20:6969-6978.
Gram, L., H. Flachs, A. Wurtz-Jorgensen, J. Parnas, and B. Andersen. 1979. Sodium valproate, serum level and clinical effect in epilepsy: a controlled study. Epilepsia. 20:303-311.
Gray, J.A. 1978. The neuropsychology of anxiety*. British Journal of Psychology. 69:417-434.
Greco, C.M., C.S. Navarro, M.R. Hunsaker, I. Maezawa, J.F. Shuler, F. Tassone, M. Delany, J.W. Au, R.F. Berman, L.W. Jin, C. Schumann, P.J. Hagerman, and R.J. Hagerman. 2011. Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. Molecular autism. 2:2.
Gur, R.C., L. Schroeder, T. Turner, C. McGrath, R.M. Chan, B.I. Turetsky, D. Alsop, J. Maldjian, and R.E. Gur. 2002. Brain activation during facial emotion processing. NeuroImage. 16:651-662.
Hagerman, R.J., C. Jackson, K. Amiri, A.C. Silverman, R. O'Connor, and W. Sobesky. 1992. Girls with fragile X syndrome: physical and neurocognitive status and outcome. Pediatrics. 89:395-400.
Haxby, J.V., L.G. Ungerleider, B. Horwitz, J.M. Maisog, S.I. Rapoport, and C.L. Grady. 1996. Face encoding and recognition in the human brain. Proceedings of the National Academy of Sciences of the United States of America. 93:922-927.
Hazlett, H.C., M. Poe, G. Gerig, R.G. Smith, J. Provenzale, A. Ross, J. Gilmore, and J. Piven. 2005. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Archives of general psychiatry. 62:1366-1376.
Henriksen, O., and S.I. Johannessen. 1982. Clinical and pharmacokinetic observations on sodium valproate - a 5-year follow-up study in 100 children with epilepsy. Acta neurologica Scandinavica. 65:504-523.
Hirase, T., J.M. Staddon, M. Saitou, Y. Ando-Akatsuka, M. Itoh, M. Furuse, K. Fujimoto, S. Tsukita, and L.L. Rubin. 1997. Occludin as a possible determinant of tight junction permeability in endothelial cells. Journal of cell science. 110 ( Pt 14):1603-1613.
Hollander, E., E. Anagnostou, W. Chaplin, K. Esposito, M.M. Haznedar, E. Licalzi, S. Wasserman, L. Soorya, and M. Buchsbaum. 2005. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biological psychiatry. 58:226-232.
Hsiao, H.Y., O.T. Mak, C.S. Yang, Y.P. Liu, K.M. Fang, and S.F. Tzeng. 2007. TNF-alpha/IFN-gamma-induced iNOS expression increased by prostaglandin E2 in rat primary astrocytes via EP2-evoked cAMP/PKA and intracellular calcium signaling. Glia. 55:214-223.
Hsieh, J., J.B. Aimone, B.K. Kaspar, T. Kuwabara, K. Nakashima, and F.H. Gage. 2004. IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. The Journal of cell biology. 164:111-122.
Ichiyama, T., K. Okada, J.M. Lipton, T. Matsubara, T. Hayashi, and S. Furukawa. 2000. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain research. 857:246-251.
Irie, F., H. Badie-Mahdavi, and Y. Yamaguchi. 2012. Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate. Proceedings of the National Academy of Sciences of the United States of America. 109:5052-5056.
Jamain, S., H. Quach, C. Betancur, M. Rastam, C. Colineaux, I.C. Gillberg, H. Soderstrom, B. Giros, M. Leboyer, C. Gillberg, and T. Bourgeron. 2003. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature genetics. 34:27-29.
Jessberger, S., R.E. Clark, N.J. Broadbent, G.D. Clemenson, Jr., A. Consiglio, D.C. Lie, L.R. Squire, and F.H. Gage. 2009. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learning & memory (Cold Spring Harbor, N.Y.). 16:147-154.
Johannessen, C.U., D. Petersen, F. Fonnum, and B. Hassel. 2001. The acute effect of valproate on cerebral energy metabolism in mice. Epilepsy research. 47:247-256.
Jones, K.L., and D.W. Smith. 1973. Recognition of the fetal alcohol syndrome in early infancy. Lancet. 302:999-1001.
Jung, G.A., J.Y. Yoon, B.S. Moon, D.H. Yang, H.Y. Kim, S.H. Lee, V. Bryja, E. Arenas, and K.Y. Choi. 2008. Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-p21Cip/WAF1 pathway. BMC cell biology. 9:66.
Juranek, J., P.A. Filipek, G.R. Berenji, C. Modahl, K. Osann, and M.A. Spence. 2006. Association Between Amygdala Volume and Anxiety Level: Magnetic Resonance Imaging (MRI) Study in Autistic Children. Journal of Child Neurology. 21:1051-1058.
Kaufmann, W.E., K.L. Cooper, S.H. Mostofsky, G.T. Capone, W.R. Kates, C.J. Newschaffer, I. Bukelis, M.H. Stump, A.E. Jann, and D.C. Lanham. 2003. Specificity of Cerebellar Vermian Abnormalities in Autism: A Quantitative Magnetic Resonance Imaging Study. Journal of Child Neurology. 18:463-470.
Kemper, T.L., and M.L. Bauman. 1993. The contribution of neuropathologic studies to the understanding of autism. Neurologic clinics. 11:175-187.
Kircher, T.T., C. Senior, M.L. Phillips, S. Rabe-Hesketh, P.J. Benson, E.T. Bullmore, M. Brammer, A. Simmons, M. Bartels, and A.S. David. 2001. Recognizing one's own face. Cognition. 78:B1-B15.
Kwon, C.H., B.W. Luikart, C.M. Powell, J. Zhou, S.A. Matheny, W. Zhang, Y. Li, S.J. Baker, and L.F. Parada. 2006. Pten regulates neuronal arborization and social interaction in mice. Neuron. 50:377-388.
Landrigan, P.J. 2010. What causes autism? Exploring the environmental contribution. Current opinion in pediatrics. 22:219-225.
Laumonnier, F., F. Bonnet-Brilhault, M. Gomot, R. Blanc, A. David, M.P. Moizard, M. Raynaud, N. Ronce, E. Lemonnier, P. Calvas, B. Laudier, J. Chelly, J.P. Fryns, H.H. Ropers, B.C. Hamel, C. Andres, C. Barthelemy, C. Moraine, and S. Briault. 2004. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. American journal of human genetics. 74:552-557.
Laurence, J.A., and S.H. Fatemi. 2005. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum (London, England). 4:206-210.
Lee, J.E., S.M. Hollenberg, L. Snider, D.L. Turner, N. Lipnick, and H. Weintraub. 1995. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science. 268:836-844.
Leiderman, D.B., M. Balish, E.B. Bromfield, and W.H. Theodore. 1991. Effect of valproate on human cerebral glucose metabolism. Epilepsia. 32:417-422.
Li, R., and R.S. El-Mallahk. 2000. A novel evidence of different mechanisms of lithium and valproate neuroprotective action on human SY5Y neuroblastoma cells: caspase-3 dependency. Neuroscience letters. 294:147-150.
Li, Y., B.W. Luikart, S. Birnbaum, J. Chen, C.H. Kwon, S.G. Kernie, R. Bassel-Duby, and L.F. Parada. 2008. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 59:399-412.
Lin, H.C., P.W. Gean, C.C. Wang, Y.H. Chan, and P.S. Chen. 2013. The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model. PLoS One. 8:e55248.
Liu, Y.P., C.S. Yang, M.C. Chen, S.H. Sun, and S.F. Tzeng. 2011. Ca(2+)-dependent reduction of glutamate aspartate transporter GLAST expression in astrocytes by P2X(7) receptor-mediated phosphoinositide 3-kinase signaling. J Neurochem. 113:213-227.
Lucke, A., T. Mayer, U. Altrup, A. Lehmenkuhler, R. Dusing, and E.J. Speckmann. 1994. Simultaneous and continuous measurement of free concentration of valproate in blood and extracellular space of rat cerebral cortex. Epilepsia. 35:922-926.
Luder, A.S., J.K. Parks, F. Frerman, and W.D. Parker, Jr. 1990. Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions. The Journal of clinical investigation. 86:1574-1581.
Markram, K., T. Rinaldi, D. La Mendola, C. Sandi, and H. Markram. 2008. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 33:901-912.
Martin, S.J., P.D. Grimwood, and R.G. Morris. 2000. Synaptic plasticity and memory: an evaluation of the hypothesis. Annual review of neuroscience. 23:649-711.
Mathis, C., P.E. Neumann, H. Gershenfeld, S.M. Paul, and J.N. Crawley. 1995. Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains. Behavior genetics. 25:557-568.
McEwen, B.S., and R.M. Sapolsky. 1995. Stress and cognitive function. Current Opinion in Neurobiology. 5:205-216.
Meunier, H., G. Carraz, Y. Neunier, P. Eymard, and M. Aimard. 1963. [Pharmacodynamic properties of N-dipropylacetic acid]. Therapie. 18:435-438.
Minshew, N.J. 1991. Indices of neural function in autism: clinical and biologic implications. Pediatrics. 87:774-780.
Miyata, T., T. Maeda, and J.E. Lee. 1999. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes & development. 13:1647-1652.
Monaco, A.P., and A.J. Bailey. 2001. Autism. The search for susceptibility genes. Lancet. 358 Suppl:S3.
Moore, S.J., P. Turnpenny, A. Quinn, S. Glover, D.J. Lloyd, T. Montgomery, and J.C. Dean. 2000. A clinical study of 57 children with fetal anticonvulsant syndromes. Journal of medical genetics. 37:489-497.
Mora, A., R.A. Gonzalez-Polo, J.M. Fuentes, G. Soler, and F. Centeno. 1999. Different mechanisms of protection against apoptosis by valproate and Li+. European journal of biochemistry / FEBS. 266:886-891.
Moura-Serra, J.D. 1990. Le diagnostic de I’autisme dans la perspective de la neuropsychiayrie de` veloppementale. In: Messerschmitt P.
Moy, S.S., J.J. Nadler, A. Perez, R.P. Barbaro, J.M. Johns, T.R. Magnuson, J. Piven, and J.N. Crawley. 2004. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes, Brain and Behavior. 3:287-302.
Moy, S.S., J.J. Nadler, N.B. Young, A. Perez, L.P. Holloway, R.P. Barbaro, J.R. Barbaro, L.M. Wilson, D.W. Threadgill, J.M. Lauder, T.R. Magnuson, and J.N. Crawley. 2007. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behavioural brain research. 176:4-20.
Muhle, R., S.V. Trentacoste, and I. Rapin. 2004. The genetics of autism. Pediatrics. 113:e472-486.
Munson J, D.G.A.R., and et al. 2006. Amygdalar volume and behavioral development in autism. Archives of general psychiatry. 63:686-693.
Nadler, J.J., S.S. Moy, G. Dold, D. Trang, N. Simmons, A. Perez, N.B. Young, R.P. Barbaro, J. Piven, T.R. Magnuson, and J.N. Crawley. 2004. Automated apparatus for quantitation of social approach behaviors in mice. Genes, brain, and behavior. 3:303-314.
Nakatani, J., K. Tamada, F. Hatanaka, S. Ise, H. Ohta, K. Inoue, S. Tomonaga, Y. Watanabe, Y.J. Chung, R. Banerjee, K. Iwamoto, T. Kato, M. Okazawa, K. Yamauchi, K. Tanda, K. Takao, T. Miyakawa, A. Bradley, and T. Takumi. 2009. Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism. Cell. 137:1235-1246.
Nau, H., and W. Loscher. 1982. Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects and gamma-aminobutyric acid (GABA) metabolism in the mouse. The Journal of pharmacology and experimental therapeutics. 220:654-659.
Nau, H., and W. Loscher. 1984. Valproic Acid and Metabolites: Pharmacological and Toxicological Studies. Epilepsia. 25:S14-S22.
Nicolson, R., T.J. DeVito, C.N. Vidal, Y. Sui, K.M. Hayashi, D.J. Drost, P.C. Williamson, N. Rajakumar, A.W. Toga, and P.M. Thompson. 2006. Detection and mapping of hippocampal abnormalities in autism. Psychiatry research. 148:11-21.
Ogawa, S., C.H. Kwon, J. Zhou, D. Koovakkattu, L.F. Parada, and C.M. Sinton. 2007. A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice. Brain research. 1168:112-123.
Palmen, S.J., and H. van Engeland. 2004. Review on structural neuroimaging findings in autism. Journal of neural transmission. 111:903-929.
Petit-Demouliere, B., F. Chenu, and M. Bourin. 2005. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology. 177:245-255.
Phiel, C.J., F. Zhang, E.Y. Huang, M.G. Guenther, M.A. Lazar, and P.S. Klein. 2001. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. The Journal of biological chemistry. 276:36734-36741.
Pierce, K., and E. Courchesne. 2001. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biological psychiatry. 49:655-664.
Pignataro, L., F.P. Varodayan, L.E. Tannenholz, and N.L. Harrison. 2009. The regulation of neuronal gene expression by alcohol. Pharmacology & therapeutics. 124:324-335.
Radatz, M., K. Ehlers, B. Yagen, M. Bialer, and H. Nau. 1998. Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. Epilepsy research. 30:41-48.
Raymond, G.V., M.L. Bauman, and T.L. Kemper. 1996. Hippocampus in autism: a Golgi analysis. Acta neuropathologica. 91:117-119.
Reynolds, C.R.G., Sam. 1999. Handbook of neurodevelopmental and genetic disorders in children, New York: The Guilford Press.
Rezayat, M., A. Roohbakhsh, M.-R. Zarrindast, R. Massoudi, and B. Djahanguiri. 2005. Cholecystokinin and GABA interaction in the dorsal hippocampus of rats in the elevated plus-maze test of anxiety. Physiology & Behavior. 84:775-782.
Rice, D., and S. Barone, Jr. 2000. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environmental health perspectives. 108 Suppl 3:511-533.
Rodier, P.M., J.L. Ingram, B. Tisdale, and V.J. Croog. 1997. Linking etiologies in humans and animal models: studies of autism. Reproductive toxicology (Elmsford, N.Y.). 11:417-422.
Rodier, P.M., J.L. Ingram, B. Tisdale, S. Nelson, and J. Romano. 1996. Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. The Journal of comparative neurology. 370:247-261.
Rosenzweig, E.S., and C.A. Barnes. 2003. Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Progress in neurobiology. 69:143-179.
Rouaux, C., I. Panteleeva, F. Rene, J.L. Gonzalez de Aguilar, A. Echaniz-Laguna, L. Dupuis, Y. Menger, A.L. Boutillier, and J.P. Loeffler. 2007. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27:5535-5545.
Sanfeliu, C., J. Sebastia, R. Cristofol, and E. Rodriguez-Farre. 2003. Neurotoxicity of organomercurial compounds. Neurotoxicity research. 5:283-305.
Sathyan, P., H.B. Golden, and R.C. Miranda. 2007. Competing interactions between micro-RNAs determine neural progenitor survival and proliferation after ethanol exposure: evidence from an ex vivo model of the fetal cerebral cortical neuroepithelium. The Journal of neuroscience : the official journal of the Society for Neuroscience. 27:8546-8557.
Schneider, T., and R. Przewlocki. 2005. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 30:80-89.
Schumann, C.M., J. Hamstra, B.L. Goodlin-Jones, L.J. Lotspeich, H. Kwon, M.H. Buonocore, C.R. Lammers, A.L. Reiss, and D.G. Amaral. 2004. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. The Journal of neuroscience : the official journal of the Society for Neuroscience. 24:6392-6401.
Scott, F.J., S. Baron-Cohen, P. Bolton, and C. Brayne. 2002. The CAST (Childhood Asperger Syndrome Test): Preliminary Development of a UK Screen for Mainstream Primary-School-Age Children. Autism. 6:9-31.
Sears, L.L., C. Vest, S. Mohamed, J. Bailey, B.J. Ranson, and J. Piven. 1999. An MRI study of the basal ganglia in autism. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 23:613-624.
Shakèd, M., K. Weissmüller, H. Svoboda, P. Hortschansky, N. Nishino, S. Wölfl, and K.L. Tucker. 2008. Histone Deacetylases Control Neurogenesis in Embryonic Brain by Inhibition of BMP2/4 Signaling. PLoS ONE. 3:e2668.
Shalom, D.B. 2003. Memory in Autism: Review and Synthesis. Cortex. 39:1129-1138.
Sheline, Y.I., P.W. Wang, M.H. Gado, J.G. Csernansky, and M.W. Vannier. 1996. Hippocampal atrophy in recurrent major depression. Proceedings of the National Academy of Sciences of the United States of America. 93:3908-3913.
Shen, S., J. Li, and P. Casaccia-Bonnefil. 2005. Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. The Journal of cell biology. 169:577-589.
Snow, W.M., K. Hartle, and T.L. Ivanco. 2008. Altered morphology of motor cortex neurons in the VPA rat model of autism. Developmental psychobiology. 50:633-639.
Squire, L.R., D.G. Amaral, and G.A. Press. 1990. Magnetic resonance imaging of the hippocampal formation and mammillary nuclei distinguish medial temporal lobe and diencephalic amnesia. The Journal of neuroscience : the official journal of the Society for Neuroscience. 10:3106-3117.
Tung, E.W., and L.M. Winn. 2011. 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. Molecular pharmacology. 80:979-987.
Vaccarino, F.M., E.L. Grigorenko, K.M. Smith, and H.E. Stevens. 2009. Regulation of cerebral cortical size and neuron number by fibroblast growth factors: implications for autism. Journal of autism and developmental disorders. 39:511-520.
van der Laan, J.W., T. de Boer, and J. Bruinvels. 1979. Di-n-propylacetate and GABA degradation. Preferential inhibition of succinic semialdehyde dehydrogenase and indirect inhibition of GABA-transaminase. J Neurochem. 32:1769-1780.
Veronica, G., S. Carmelo, P. Stefano, B. Vincenza, F. Anna, G. Carmela, M. Silvia, H. Alexandra, D.G. Eckart, R.F. Francesca, C. Paolo, and P. Barbara. 2010. TrkB/BDNF-Dependent Striatal Plasticity and Behavior in a Genetic Model of Epilepsy: Modulation by Valproic Acid. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 35:1531-1540.
Voorhees, C.V. 1986. Handbook of behavioral teratology. New York: Plenum Press.
Vorstman, J.A., W.G. Staal, E. van Daalen, H. van Engeland, P.F. Hochstenbach, and L. Franke. 2006. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Molecular psychiatry. 11:1, 18-28.
Wagner, G.C., K.R. Reuhl, M. Cheh, P. McRae, and A.K. Halladay. 2006. A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. Journal of autism and developmental disorders. 36:779-793.
Waly, M., H. Olteanu, R. Banerjee, S.W. Choi, J.B. Mason, B.S. Parker, S. Sukumar, S. Shim, A. Sharma, J.M. Benzecry, V.A. Power-Charnitsky, and R.C. Deth. 2004. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Molecular psychiatry. 9:358-370.
Wegiel, J., I. Kuchna, K. Nowicki, H. Imaki, J. Wegiel, E. Marchi, S. Ma, A. Chauhan, V. Chauhan, T. Bobrowicz, M. Leon, L.S. Louis, I. Cohen, E. London, W.T. Brown, and T. Wisniewski. 2010. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta neuropathologica. 119:755-770.
Xin, M., T. Yue, Z. Ma, F.F. Wu, A. Gow, and Q.R. Lu. 2005. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 25:1354-1365.
Ye, F., Y. Chen, T. Hoang, R.L. Montgomery, X.H. Zhao, H. Bu, T. Hu, M.M. Taketo, J.H. van Es, H. Clevers, J. Hsieh, R. Bassel-Duby, E.N. Olson, and Q.R. Lu. 2009. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction. Nature neuroscience. 12:829-838.
Zeise, M.L., S. Kasparow, and W. Zieglgansberger. 1991. Valproate suppresses N-methyl-D-aspartate-evoked, transient depolarizations in the rat neocortex in vitro. Brain research. 544:345-348.
Zheng, H., P.-Y. Law, and H.H. Loh. 2012. Non-coding RNAs regulating morphine function: with emphasis on the in vivo and in vitro functions of miR-190. Frontiers in Genetics. 3.
Zoghbi, H.Y. 2003. Postnatal neurodevelopmental disorders: meeting at the synapse? Science. 302:826-830.