review article what we have learned about autism …

Hindawi Publishing CorporationPathology Research InternationalVolume 2013 Article ID 712758 8 pageshttpdxdoiorg1011552013712758

Review ArticleWhat We Have Learned about Autism Spectrum Disorder fromValproic Acid

Taylor Chomiak Nathanael Turner and Bin Hu

Department of Clinical Neurosciences Hotchkiss Brain Institute Faculty of Medicine University of Calgary3280 Hospital Drive NW Calgary AB Canada T2N 4N1

Correspondence should be addressed to Taylor Chomiak tgchomiaucalgaryca

Received 9 July 2013 Revised 16 October 2013 Accepted 17 October 2013

Academic Editor Piero Tosi

Copyright copy 2013 Taylor Chomiak et alThis is an open access article distributed under theCreativeCommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Two recent epidemiological investigations in children exposed to valproic acid (VPA) treatment in utero have reported a significantrisk associated with neurodevelopmental disorders and autism spectrum disorder (ASD) in particular Parallel to this work thereis a growing body of animal research literature using VPA as an animal model of ASD In this focused review we first summarizethe epidemiological evidence linking VPA to ASD and then comment on two important neurobiological findings linking VPA toASD clinicopathology namely accelerated or early brain overgrowth and hyperexcitable networks Improving our understandingof how the drug VPA can alter early development of neurological systems will ultimately improve our understanding of ASD

1 Introduction

The core clinicopathology of autism spectrum disorder(ASD) is currently thought to be characterized by acceler-ated or early brain tissue overgrowth in regions involvedin emotional social and communication functions [1ndash6]Although much of the earlier evidence regarding acceleratedor early brain overgrowth was based on head circumferencemeasurements which may not be as robust as previouslythought [7] (but see [8]) more recent longitudinal brainimaging studies have provided further evidence of thisabnormal pattern of brain growth in ASD [3 6] In factabnormal pathological overgrowth in ASD may even persistinto adulthood in certain brain regions [9]

Exposure to exogenous chemicals during pregnancy caninterfere with cortical development and the maturation ofoffspring One such exogenous chemical is the short chainfatty acid valproic acid (VPA) VPA is a drug used in humansprimarily for epilepsy and seizure control although it hasbeen used in many nonepileptic conditions as well [10]Based on several case studies and small-scale population-based studies in humans [11ndash16] in addition to mountingexperimental evidence in animals [17ndash32] VPA has knownteratogenicity and has long been suspected as a risk factor

for ASD This year however both a prospective study and alarge-scale population-based study were published providingthe most substantial evidence to date linking prenatal VPAexposure to an increased risk of ASD [33 34] Thus in thispaper we will review epidemiological evidence linking VPAto ASD and will discuss two promising leads in the study ofASD in light of human clinical findings and the valproic acidanimal model of ASD

2 Valproic Acid and ASDEpidemiological Evidence

Previous links between the antiepileptic drug VPA andASD have been found and explored in several case studiesand retrospective studies VPA has long been known tocause physical malformations and developmental disabilitiesfeatures of the clinical entity termed fetal valproate syndrome(FVS) Laegreid and colleagues in a 1993 study examinedseven children with FVS two of which were also exposedto benzodiazepines Two of the seven cases showed autistictraits with 2 more showing marked developmental delays[16] The next year Christianson et al published a case

2 Pathology Research International

study describing two sibling pairs all having FVS to variousdegrees with one having been diagnosed with infantileautism [11] A second case of a boy with FVS and ASDwas reported by Williams et al in 1997 followed up with 5more cases described by the same authors in 2001 [12 13]Several larger retrospective studies have also been publishedproviding further support that in utero VPA exposure andfetal valproate syndromemay be linked to an increased risk ofASD where for example it has been reported that the rate ofASD in the children of VPA-treated mothers may be roughlyeight times larger than that of the general population [14 1535] Nevertheless many of these studies had mentioned theneed for future study to confirm the association betweenVPAand ASD

A recently published prospective cohort study byBromleyet al [33] explored the relationship between prenatal expo-sure to anti-epileptic drugs (including VPA) and the riskof neurodevelopmental disorders such as ASD ADHD andDyspraxia They performed an 11-year study observing thephysical and cognitive development of 415 children bornto mothers with epilepsy and nonepileptic controls with afinal outcome of neurodevelopmental diagnosis by 6 yearsof age Their results showed a significant increase in therisk of neurodevelopmental disorders in those women takingVPA during pregnancy with autism being the most frequentdiagnosis The researchers also suspected a dose-dependentmechanism of VPA action but were not able to show it withsignificance in the study due to low numbers of motherstaking VPA Although this study had a fairly small cohortand a relatively early endpoint (the average age of diagnosis ofASD in theUK is 5ndash11 years of age) it was the first prospectivestudy to explore the relationship of VPA to ASD [33]

A much larger and detailed population-based study byChristensen et al [34] that focused more on ASD than otherneurodevelopmental disorders was also published this yearThe large sample (655615 children) and thorough controlof the study provide the strongest evidence to date on therelationship between VPA andASD Data were from childrenborn in Denmark from 1996 through 2006 over 14 yearsuntil the end of 2010 In their analysis they controlled forother known risk factors of ASD and potential confounderssuch as parental psychiatric disease parental age at concep-tion congenital malformations and maternal epilepsy Theydivided the outcomes as Autism SpectrumDisorder (ASD) orchildhood autism (the most severe diagnosis simply referredto as ldquoautismrdquo) and reported absolute risks over the 14 yearsand hazard ratios (HR) for each The absolute risks for allchildren studied for ASD and autism were 153 and 048respectively whereas for those exposed to VPA in uterothe risks were 442 (HR 29) and 25 (HR 52) In facteven when looking at all stratifications and controls it wasconcluded that there was a significantly increased risk ofchildren developing either ASD or autism in women takingVPA during pregnancy [34]

Accumulating epidemiological studies have shown anincreased risk of children developing a neurodevelopmentaldisorder and ASD in particular if their mothers take VPAduring pregnancy These findings should encourage a dis-cussion on the risks and benefits of the treatment during

pregnancy and provide an opportunity to explore how thischemical can alter early developing biological systems thatmay relate to ASD in animal models This may facilitatethe discovery of other VPA-like substances that may subse-quently prove to be environmental or nutritional risk factorsfor the development ofASD and these could further elucidatethe role of exogenous chemicals on ASD pathology Theauthors of the two recent papers discussed above also noted aneed to define the mechanism behind the increased risk ofASD with VPA exposure Several questions arise as to therelationship between environmental exposure to chemicalssuch asVPA in themanifestation ofASD [33 34] Christensenet al suggested several mechanisms by which VPA mayincrease the risk of ASD that need further study includinginterference in neurotransmitter function neuronal apopto-sis or plasticity histone deacetylase inhibition and disruptionof folic acid metabolism [34] Studying the effects of VPAon biological tissue will provide many avenues to explore thepossible mechanism(s) of ASD

3 Valproic Acid Rodent Model of ASD

Themodel of VPA exposure proposed by Rodier et al in 1996is one of the most frequently studied animal models of ASD[36 37] (also see [38] for review) As reviewed by Dufour-Rainfray et al this model exhibits many of the structural andbehavioural features that can be observed in ASD patients[39] For example rats exposed to VPA in utero can exhibitphysical malformations (eg ear malformations) which havebeen compared to similar abnormalities that have beenobserved in some autistic patients (eg posterior rotationof the outer ear) [39] Furthermore several independentlaboratories have also shown that prenatal VPA exposure canlead to behavioral abnormalities that are strikingly similarto those observed in autistic patients including decreasedsocial interactions and sensitivity to pain increased sensi-tivity to nonpainful stimuli repetitivestereotypic-like activ-ity increased anxiety abnormally high and longer lastingfear memories which are over-generalized and harder toextinguish and changes in specific types of pup ultrasonicvocalizations [17ndash28 30 31 39] At the cellular level recentmorphological data has also suggested that a decrease in spinedensity in forebrain structures may be a substrate for distalhypo-connectivity while the increase in dendritic lengthmight support the enhancement of local hyperconnectivity[40] As pointed out by the authors this notion is consistentwith the ldquointense worldrdquo theory of ASD which postulates amain neuropathology characterized by hyperfunctioning oflocal neural microcircuits [40ndash42]

An animal model to be considered as a relevant modelof a psychiatric condition described in humans should fitseveral criteria usually described as construct face and pre-dictive validity [43] Although the effects of VPA have beentested in rodents formany years only relatively recently it hasbeen used to model ASD in rodents for studying ASD-likebehavioural features and potential treatment interventions[1 26] Roullet et al have noted that the VPA model exhibitsboth construct and face validity [38] and recent work has

Pathology Research International 3

now provided evidence that it may also exhibit predictivevalidity [26 44] For example Schneider et al previouslyreported that environmental enrichment includingmultisen-sory stimulation reversed almost all behavioral alterationsobserved in pups exposed to VPA in utero [26] while Wooand Leon have recently shown in a randomized controlledtrial that environmental enrichment in the form of multiplesensorimotor stimuli was also effective in ameliorating someof the symptoms in autistic children [44]

It has been suggested that methodological issues mayhave limited the effectiveness of utilizing the prenatal VPArodent model to study ASD [45] Interestingly similar to theprenatalmodel manyASD-like behavioural and pathologicalfeatures have also been observed with VPA exposure duringthe early postnatal period (equivalent to the third trimesterand perinatal period in humans) as previously shown byYochum et al [46ndash49] This suggests a mechanism that iseffective over different developmental time points and mayoffer an additional approach for studying ASD in rodentsIndeed the postnatal VPAmodel may partly be explained bythe clinical observation that the maternal serum VPA free-fraction increases in the third trimester and is highest at birth[50] This is consistent with the idea that bioavailability mayplay an important role in VPA teratogenicity and that pre-and early postnatal VPA exposure may be quite useful instudying the effects of VPA to help elucidate neuropatholog-ical mechanisms of ASD [47] For instance VPA exposureduring prenatal and early postnatal periods in rodents canlead to accelerated or early brain overgrowth that is reminis-cent of that observed in humans Prenatal VPA exposure onthe one hand has been shown to induce a more generalizedpathology and can induce macrocephaly in rat brain [51]while early postnatal VPA exposure on the other hand hasbeen suggested to induce a more regionally selective patternof aberrant overgrowth that may be particularly prominentin the temporal association cortex [49] Thus while it hasbeen reported that the period of exposure to VPA that islikely to result in ASD is the first trimester of pregnancy thepossibility that ASD can also result from later effects shouldnot be excluded [39]

4 Valproic Acid and Epigenetic Regulation

Dysregulated biochemical pathways can have a profoundimpact on key cellular processes that may ultimately alterneuronal and network developmental trajectories We knowthat the coordinated execution of gene programs involved inneural network maturation is highly regulated by epigeneticprocesses and that many biochemical pathways can convergeto influence these processes [52ndash55] (Figure 1) Some of themechanisms that may be involved include histone acetyla-tion histone methylation and possibly DNA methylation

Valproic acid is a commonly used antiepileptic drug [39]Classically the mechanism of action of VPA has focused onincreases in brain concentrations of gamma-aminobutyricacid (GABA) the major inhibitory neurotransmitter [39]but has also included modulation of voltage-gated sodium

channels and glutamatergic signaling [59] However it waspreviously shown in an animal model of seizure that VPAtreatment did not significantly affect seizure strength orfrequency for the first several days following induction butdid interestingly protect the animals from seizure-inducedcognitive impairment [60] The authors concluded that theirresults could be explained at least partially by histonedeacetylase (HDAC) inhibition [60] In fact several studieshave since been published supporting the notion that VPAmay block HDAC activity in neurons [52 58 61]

Histone deacetylases (HDACs) play an important role inregulating gene transcription and phenotype differentiation[53ndash55] For example MacDonald and Roskams reportedspecific expression patterns of HDAC1 and HDAC2 (bothclass I HDACs) in the murine brain at multiple developmen-tal ages HDAC1 is expressed in neural stem cellsprogenitorsand glia while HDAC2 is upregulated in postmitotic neu-roblasts and neurons but not in fully differentiated glia [62]HDAC modulation in different cell types and at differentmaturational time points may therefore lead to dramaticallydifferent outcomes and may help to explain why HDACinhibition in adulthood can improve ASD-like symptoms inrodents exposed to VPA in utero [63]

VPA is a nonselective HDAC inhibitor Class I HDACswhich include HDAC1 and HDAC2 are expressed in theCNS and VPA has the net effect of inhibiting their activityvia different mechanisms VPA inhibits HDAC1 throughinteraction with the enzymersquos catalytic site while VPAinduces proteasomal degradation of HDAC2 [64 65] This isimportant as inhibition of class IHDACs can lead to increasesin synapse numbers and a robust facilitation of excitatorysynapse maturation [52] Furthermore VPA can also lead toincreased neurite growth and promote neural proliferation[51 66] both of which are thought to contribute to theaccelerated or early overgrowth observed in ASD [1]

ASD structural pathology is regionally selective exhibit-ing changes that are prominent in the prefrontal and temporalassociation cortices [1ndash3] that can even persist into adulthood[9] These areas have been found to exhibit a slow and pro-tracted endogenous pattern of development under normalconditions remaining relatively immature well into postnatallife [67ndash72] This pattern of maturation appears to be neededfor appropriate cognitive development and allowing forthe maturation and stabilization of lower-order networkswith which to build upon [73ndash75] However the protractedmaturation pattern of these prefrontal and temporal areasmay confer an enhanced vulnerability to HDAC inhibitioncompared to networks that have already attained fullmaturity[1] This vulnerability may lead to prominent increases inthe structural assembly of synapses and growth of neuralnetworks both of which are thought to contribute to theunderlying clinicopathology of ASD [1 76]

Histone methylation is another important epigeneticmechanism related to histone acetylation that can regulategene transcription developmental gene programs and cellu-lar phenotype [55 77 78] Much like that of histone acetyla-tion it has been proposed that histone methylation may bereversible dynamic and also important in the teratogenicityof VPA [78] For example Tung and Winn reported that not


Ac Me Ac

Pol

VPA

Nucleus

Me

Cytosol

Metabotropic receptors

Ionotropic receptors

Voltage-gated ion channels

Neuronal growth

Network excitabilityMore neurons

Other 2nd messengersystems

Ca++

Figure 1 A schematic of some key molecular and cellular changes associated with VPA related to ASD neuropathology Commonclinicopathology associated with ASD is accelerated or early brain overgrowth and increased network excitability Early or acceleratedovergrowthmay result frommore synapses increased denritic growth andor increased number of cells while increased network excitabilitymay result fromhyperconnectivity andor hyperplasticity ofmicrocircuits presumably driven by synapticmechanisms (ie enhanced paired-pulse facilitation and long-term potentiation) that have been shown in rat brain both in vitro and in vivo following prenatal VPA exposure[56 57] All of these aspects are also likely regulated by histone acetylation (orange circles ldquoAcrdquo) andor histone methylation (green circlesldquoMerdquo) and possibly DNA methylation (DNA methylation not shown) VPA has been shown to increase histone acetylation and histonemethylation that can promote gene activation (symbolized by blue circle ldquoPolrdquo RNApolymerase)WhileVPAmaydisrupt the balance betweenexcitatory and inhibitory neuronal activities through histone acetylation modulation [58] the role of histone methylation on VPA-relatedASD neuropathology is much less clear Increased connectivity and network excitability may further influence this process by activatingmetabotropic ionotropic and voltage-gated ion channels and subsequent intracellular signaling cascades

only did in utero exposure to VPA lead to HDAC inhibitionand increased histone acetylation of mouse fetal tissue butit was also associated with changes in histone methylation[78] In fact this study found significant increases in di-and trimethylated histone 3-K4 and significant decreases inmonomethylated histone 3-K9 which may represent sitesinvolved in gene activation and repression respectively [77]Indeed these epigenetic changes are likely involved in themultiple genes that can be influenced by early VPA exposure[58]

Adding another layer of complexity to the epigeneticcontrol of gene regulation is DNAmethylation wheremethylgroups covalently bound to the 51015840 position of cytosine projectinto the major groove of DNA thus inhibiting the binding oftranscription factors [78] While there is interplay betweenDNA methylation and histone acetylation [79] somewhatsurprisingly the significance of DNAmethylation as a mech-anism of VPA-induced teratogenesis remains debatable [78]Thus the role VPA plays on DNA methylation and theinterplay between DNA methylation and histone acetylationwill be an important area for future research

5 Valproic Acid Overconnectivityand Hyperexcitable Networks

Clinically apparent seizures are not uncommon in ASD [80]While there has been a long standing association betweenASD and seizure even children that do not present with clin-ical seizure can exhibit subclinical seizure and epileptiformelectroencephalographic (EEG) abnormalities [80 81] Thusit is postulated that accelerated or early brain overgrowth isaccompanied by pathological changes in network excitability

The rodent VPA model of ASD allows for intrusiveelectrophysiological study of living tissue unavailable inhumans to uncover the nature and potential causes of thesesuspected electrophysiological abnormalities One prevailingtheory of ASD the ldquointense worldrdquo theory [41 42] has beenrefined through the study of theVPA ratmodel andpostulatesthat several areas of the brain including the prefrontal cortexand amygdala display hyperreactivity of the microcircuitryof pyramidal cells compared to controls [22 23 41 42 5657] The amygdala bares particular relevance for exampleas it has been functionally related to ASD due to its role in


socioemotional behaviour and can also exhibit enlargementand hyperactivation in autistic children [82 83] Markramrsquosgroup has shown enhanced fear memories enhanced feargeneralization and impaired fear extinction in prenatallyexposed VPA treated rats along with the other ASD-likebehavioural phenotypes [23] As well electrophysiologicaldata from lateral amygdaloid nucleus slices showed increasedreactivity to stimulation increased long-term potentiationand impaired inhibition [23] A similar result was found byLin et al as they also reported hyperexcitability and enhancedLTP in amygdala lateral nucleus pyramidal neurons followingprenatal exposure to VPA [17] These authors stated that theincreased ratio of synaptic excitationinhibition in the amyg-dala might be associated with the characteristic behaviourin this ASD model [17] which was reiterated by Kim et albased on their own work showing increased expression ofglutamatergic proteins in prefrontal networks of postnatalbrains of rat offspring exposed to VPA in utero [84] Finallyas impairments in the GABAergic system may critically con-tribute to an increased synaptic excitationinhibition ratio anadditional mechanism may also involve reduced GABAergicinhibition as recently shown in the temporal cortex of ratpups following prenatal VPA exposure [85]

Although functional imaging studies of the autistic brainhave long suggested decreased activity these recent find-ings from the VPA model propose an alternate explana-tion wherein electrophysiological abnormalities may causenetwork hyperactivity within hyperconnected microcircuits[22 42 57] Indeed a recent imaging study has shownhyperconnectivity in several large-scale brain networks ofchildren with ASD [86] While previous functional magneticresonance imaging (fMRI) studies have been somewhatcontradictory these recent findings suggest that furtherresearch into brain network connectivity may lead to a betterunderstanding of the pathology of ASD in the brain [86]

Furthermore prenatal VPA exposure has been shown toincrease NMDA receptor NR2A and NR2B subunits [22]with NR2A being important in epileptogenesis [87] Con-sequently this enhanced activity may subsequently lead togreater activity-dependent processes involved in controllingstructural aspects neuronal and synaptic networkmaturationand growth (Figure 1) For example it has been shownthat activity-induced NR2A activation can lead to increasedbrain-derived neurotrophic factor (BDNF) expression [87]Thus given that BDNF is important in neuronal development[88ndash90] and epileptogenesis [91] this may be one of severalsignaling pathways involved in the clinicopathology of ASD

While activity modulates not only structural aspects ofneuronal connectivity such as dendritic branching and spineformation it can also influence the neurochemical landscapeof the neural network For example an emerging bodyof the literature is now providing mechanistic insight intoneurotransmitter specification and the role of electrical activ-ity in the developing nervous system [92ndash94] Consequentlyalterations in the proportions of excitatory and inhibitoryneural transmitter phenotypes may play a very importantrole in the pathophysiology associated with ASD [95] Anumber of neurodevelopmental processes ranging from earlyevents of cell proliferation and differentiation to late events

involving maturation of the dendritic arbors and synapsescan all be influenced by activity [92 94] Thus furtherstudy on the electrophysiological changes associated withrodent brains exposed to VPA is likely to uncover convergentmolecular pathway(s) that drive these changes

6 Conclusion

Based on accumulating clinical data it is becoming increas-ingly clear that VPA is an important risk factor associatedwith ASD In addition a growing body of animal literatureis also showing that VPA can lead to ASD-like features inrodents Moreover published work suggests that the VPAmodel of ASD appears to exhibit all elements of a relevantmodel namely construct face and predictive validity andtherefore is likely to prove useful in elucidating mechanismsof ASD clinicopathology It is also important to note that thesignificance of the two recent epidemiological studies dis-cussed in this paper may also lie in the potential of revealingVPA-like environmental or nutritional substances that couldincrease the risk of ASD For example it was recently shownthat in certain cell types global histone acetylation andHDACactivity could be regulated by metabolites of intermediatemetabolism [96] Based on studies primarily in nonneuronalcells it is also now evident that other agents includingthose in the human diet can be converted by metabolismto intermediates that can influence HDAC activity [96 97]Thus improving our understanding of how VPA and VPA-like compounds can alter early nervous system developmentwill ultimately improve our understanding of ASD

Acknowledgments

The authors would like to thank Johanna Hung for help-ful comments on an earlier version of the paper and DrJeffrey Buchhalter for insightful discussion This study wassupported by Canadian Institutes of Health Research andCIHR Regenerative Medicine Initiative Nathanael Turneris supported by a PURE studentship Taylor Chomiak andNathanael Turner are cofirst authors

References

[1] T Chomiak and B Hu ldquoAlterations of neocortical developmentand maturation in autism insight from valproic acid exposureand animal models of autismrdquo Neurotoxicology and Teratologyvol 36 pp 57ndash66 2013

[2] E Courchesne K Pierce CM Schumann et al ldquoMapping earlybrain development in autismrdquo Neuron vol 56 no 2 pp 399ndash413 2007

[3] C M Schumann C S Bloss C C Barnes et al ldquoLongitudinalmagnetic resonance imaging study of cortical developmentthrough early childhood in autismrdquo Journal of Neuroscience vol30 no 12 pp 4419ndash4427 2010

[4] D G Amaral C M Schumann and C W Nordahl ldquoNeu-roanatomy of autismrdquo Trends in Neurosciences vol 31 no 3 pp137ndash145 2008

[5] R Adolphs ldquoThe neurobiology of social cognitionrdquo CurrentOpinion in Neurobiology vol 11 no 2 pp 231ndash239 2001


[6] H CHazlettMD Poe G Gerig et al ldquoEarly brain overgrowthin autism associated with an increase in cortical surface areabefore age 2 yearsrdquo Archives of General Psychiatry vol 68 no5 pp 467ndash476 2011

[7] A Raznahan G L Wallace L Antezana et al ldquoComparedto what Early brain overgrowth in autism and the perils ofpopulation normsrdquo Biol Psychiatry vol 74 no 8 pp 563ndash5752013

[8] D R Morhardt W Barrow M Jaworski and P J AccardoldquoHead circumference in young childrenwith autism the impactof different head circumference chartsrdquo Journal of Child Neurol-ogy 2013

[9] C Ecker J Suckling S C Deoni et al ldquoBrain anatomy andits relationship to behavior in adults with autism spectrumdisorder a multicenter magnetic resonance imaging studyrdquoArchives of General Psychiatry vol 69 no 2 pp 195ndash209 2012

[10] J A Balfour and HM Bryson ldquoValproic acidrdquo CNS Drugs vol2 no 2 pp 144ndash173 1994

[11] A L Christianson N Chesler and J G R Kromberg ldquoFetalvalproate syndrome clinical and neuro-developmental featuresin two sibling pairsrdquoDevelopmental Medicine and Child Neurol-ogy vol 36 no 4 pp 361ndash369 1994

[12] GWilliams J King M Cunningham M Stephan B Kerr andJ H Hersh ldquoFetal valproate syndrome and autism additionalevidence of an associationrdquo Developmental Medicine and ChildNeurology vol 43 no 3 pp 202ndash206 2001

[13] P G Williams and J H Hersh ldquoA male with fetal valproatesyndrome and autismrdquo Developmental Medicine and ChildNeurology vol 39 no 9 pp 632ndash634 1997

[14] S J Moore P Turnpenny A Quinn et al ldquoA clinical studyof 57 children with fetal anticonvulsant syndromesrdquo Journal ofMedical Genetics vol 37 no 7 pp 489ndash497 2000

[15] A D Rasalam H Hailey J H G Williams et al ldquoCharac-teristics of fetal anticonvulsant syndrome associated autisticdisorderrdquoDevelopmental Medicine and Child Neurology vol 47no 8 pp 551ndash555 2005

[16] L Laegreid M Kyllerman T Hedner B Hagberg and GViggedahl ldquoBenzodiazepine amplification of valproate terato-genic effects in children of mothers with absence epilepsyrdquoNeuropediatrics vol 24 no 2 pp 88ndash92 1993

[17] HC Lin PWGeanC-CWang YHChan andPChen ldquoTheamygdala excitatoryinhibitory balance in a valproate-inducedrat autism modelrdquo PLoS ONE vol 8 no 1 Article ID e552482013

[18] V Bambini-Junior L Rodrigues G A Behr J C F MoreiraR Riesgo and C Gottfried ldquoAnimal model of autism inducedby prenatal exposure to valproate behavioral changes and liverparametersrdquo Brain Research vol 1408 pp 8ndash16 2011

[19] P E Binkerd J M Rowland H Nau and A G HendrickxldquoEvaluation of valproic acid (VPA) developmental toxicity andpharmacokinetics in Sprague-Dawley ratsrdquo Fundamental andApplied Toxicology vol 11 no 3 pp 485ndash493 1988

[20] D Dufour-Rainfray P Vourcrsquoh A Le Guisquet et al ldquoBehaviorand serotonergic disorders in rats exposed prenatally to val-proate a model for autismrdquo Neuroscience Letters vol 470 no1 pp 55ndash59 2010

[21] K C Kim P Kim H S Go et al ldquoThe critical period ofvalproate exposure to induce autistic symptoms in Sprague-Dawley ratsrdquo Toxicology Letters vol 201 no 2 pp 137ndash142 2011

[22] T Rinaldi K Kulangara K Antoniello and H Markram ldquoEle-vated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic

acidrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 104 no 33 pp 13501ndash13506 2007

[23] K Markram T Rinaldi D L Mendola C Sandi and HMarkram ldquoAbnormal fear conditioning and amygdala process-ing in an animal model of autismrdquo Neuropsychopharmacologyvol 33 no 4 pp 901ndash912 2008

[24] F I Roullet L Wollaston D deCatanzaro and J A FosterldquoBehavioral and molecular changes in the mouse in responseto prenatal exposure to the anti-epileptic drug valproic acidrdquoNeuroscience vol 170 no 2 pp 514ndash522 2010

[25] T Schneider and R Przewłocki ldquoBehavioral alterations inrats prenatally to valproic acid animal model of autismrdquoNeuropsychopharmacology vol 30 no 1 pp 80ndash89 2005

[26] T Schneider J Turczak and R Przewłocki ldquoEnvironmentalenrichment reverses behavioral alterations in rats prenatallyexposed to valproic acid issues for a therapeutic approach inautismrdquo Neuropsychopharmacology vol 31 no 1 pp 36ndash462006

[27] T Schneider A Roman A Basta-Kaim et al ldquoGender-specificbehavioral and immunological alterations in an animal modelof autism induced by prenatal exposure to valproic acidrdquoPsychoneuroendocrinology vol 33 no 6 pp 728ndash740 2008

[28] C V Vorhees ldquoBehavioral teratogenicity of valproic acidselective effects on behavior after prenatal exposure to ratsrdquoPsychopharmacology vol 92 no 2 pp 173ndash179 1987

[29] C V Vorhees ldquoTeratogenicity and developmental toxicity ofvalproic acid in ratsrdquo Teratology vol 35 no 2 pp 195ndash202 1987

[30] G C Wagner K R Reuhl M Cheh P McRae and A KHalladay ldquoA newneurobehavioralmodel of autism inmice pre-and postnatal exposure to sodium valproaterdquo Journal of Autismand Developmental Disorders vol 36 no 6 pp 779ndash793 2006

[31] A C Felix-Ortiz and M Febo ldquoGestational valproate altersBOLD activation in response to complex social and primarysensory stimulirdquo PLoSONE vol 7 no 5 Article ID e37313 2012

[32] R Mychasiuk S Richards A Nakahashi B Kolb and R GibbldquoEffects of rat prenatal exposure to valproic acid on behaviourand neuro-anatomyrdquo Developmental Neuroscience vol 34 pp268ndash276 2012

[33] R L Bromley G E Mawer M Briggs et al ldquoThe prevalence ofneurodevelopmental disorders in children prenatally exposedto antiepileptic drugsrdquo Journal of Neurology Neurosurgery ampPsychiatry vol 84 no 6 pp 637ndash643 2013

[34] J Christensen T K Groslashnborg M J Soslashrensen et al ldquoPrenatalvalproate exposure and risk of autism spectrum disorders andchildhood autismrdquo Journal of the AmericanMedical Associationvol 309 no 16 pp 1696ndash1703 2013

[35] J C Dean H Hailey S J Moore D J Lloyd P D Turnpennyand J Little ldquoLong term health and neurodevelopment inchildren exposed to antiepileptic drugs before birthrdquo Journal ofMedical Genetics vol 39 no 4 pp 251ndash259 2002

[36] P M Rodier J L Ingram B Tisdale S Nelson and J RomanoldquoEmbryological origin for autism developmental anomaliesof the cranial nerve motor nucleirdquo Journal of ComparativeNeurology vol 370 no 2 pp 247ndash261 1996

[37] P M Rodier J L Ingram B Tisdale and V J Croog ldquoLinkingetiologies in humans and animal models studies of autismrdquoReproductive Toxicology vol 11 no 2-3 pp 417ndash422 1997

[38] F I Roullet J K Lai and J A Foster ldquoIn Utero exposureto valproic acid and autismmdasha current review of clinical andanimal studiesrdquoNeurotoxicology and Teratology vol 36 pp 47ndash56 2013


[39] D Dufour-Rainfray P Vourcrsquoh S Tourlet D Guilloteau SChalon and C R Andres ldquoFetal exposure to teratogensevidence of genes involved in autismrdquo Neuroscience and Biobe-havioral Reviews vol 35 no 5 pp 1254ndash1265 2011

[40] M E Bringas F N Carvajal-Floresa T A Lopez-RamırezM Atzori and G Flores ldquoRearrangement of the dendriticmorphology in limbic regions and altered exploratory behaviorin a rat model of autism spectrum disorderrdquo Neuroscience vol241 pp 170ndash187 2013

[41] K Markram and H Markram ldquoThe intense world theory-aunifying theory of the neurobiology of autismrdquo Frontiers inHuman Neuroscience vol 4 p 224 2010

[42] H Markram T Rinaldi and K Markram ldquoThe intense worldsyndrome-an alternative hypothesis for autismrdquo Frontiers inNeuroscience vol 1 no 1 pp 77ndash96 2007

[43] C Belzung S Leman P Vourcrsquoh and C Andres ldquoRodentmodels for autism a critical reviewrdquoDrug Discovery Today vol2 no 2 pp 93ndash101 2005

[44] C C Woo and M Leon ldquoEnvironmental enrichment as aneffective treatment for autism a randomized controlled trialrdquoBehavioral Neuroscience vol 127 no 4 pp 487ndash497 2013

[45] S E Lazic and L Essioux ldquoImproving basic and translationalscience by accounting for litter-to-litter variation in animalmodelsrdquo BMC Neuroscience vol 14 p 37 2013

[46] A Oguchi-Katayama A Monma Y Sekino T Moriguchi andK Sato ldquoComparative gene expression analysis of the amygdalain autistic ratmodels produced by pre- andpost-natal exposuresto valproic acidrdquo Journal of Toxicological Sciences vol 38 no 3pp 391ndash402 2013

[47] S Reynolds A Millette and D P Devine ldquoSensory and motorcharacterization in the postnatal valproate rat model of autismrdquoDevelopmental Neuroscience vol 34 no 2-3 pp 258ndash267 2012

[48] C L Yochum P Dowling K R Reuhl G C Wagner andX Ming ldquoVPA-induced apoptosis and behavioral deficits inneonatal micerdquo Brain Research vol 1203 pp 126ndash132 2008

[49] T Chomiak V Karnik E Block and B Hu ldquoAltering thetrajectory of early postnatal cortical development can lead tostructural and behavioural features of autismrdquo BMC Neuro-science vol 11 p 102 2010

[50] E Jager-Roman A Deichl and S Jakob ldquoFetal growth majormalformations andminor anomalies in infants born to womenreceiving valproic acidrdquo Journal of Pediatrics vol 108 no 6 pp997ndash1004 1986

[51] H S Go K C Kim C S Choi et al ldquoPrenatal exposureto valproic acid increases the neural progenitor cell pool andinduces macrocephaly in rat brain via a mechanism involvingthe GSK-3betabeta-catenin pathwayrdquoNeuropharmacology vol63 no 6 pp 1028ndash1041 2012

[52] M W Akhtar J Raingo E D Nelson et al ldquoHistone deacety-lases 1 and 2 form a developmental switch that controls excita-tory synapse maturation and functionrdquo Journal of Neurosciencevol 29 no 25 pp 8288ndash8297 2009

[53] V Balasubramaniyan E Boddeke R Bakels et al ldquoEffects ofhistone deacetylation inhibition on neuronal differentiation ofembryonic mouse neural stem cellsrdquo Neuroscience vol 143 no4 pp 939ndash951 2006

[54] J Hsieh and F H Gage ldquoEpigenetic control of neural stem cellfaterdquo Current Opinion in Genetics and Development vol 14 no5 pp 461ndash469 2004

[55] J Hsieh and F H Gage ldquoChromatin remodeling in neuraldevelopment and plasticityrdquo Current Opinion in Cell Biologyvol 17 no 6 pp 664ndash671 2005

[56] L Sui and M Chen ldquoPrenatal exposure to valproic acidenhances synaptic plasticity in the medial prefrontal cortex andfear memoriesrdquo Brain Research Bulletin vol 87 no 6 pp 556ndash563 2012

[57] T Rinaldi C Perrodin and H Markram ldquoHyper-connectivityand hyper-plasticity in the medial prefrontal cortex in thevalproic Acid animal model of autismrdquo Frontiers in NeuralCircuits vol 2 p 4 2008

[58] M Fukuchi T Nii N Ishimaru et al ldquoValproic acid inducesup- or down-regulation of gene expression responsible forthe neuronal excitation and inhibition in rat cortical neuronsthrough its epigenetic actionsrdquo Neuroscience Research vol 65no 1 pp 35ndash43 2009

[59] B Monti E Polazzi and A Contestabile ldquoBiochemical molec-ular and epigenetic mechanisms of valproic acid neuroprotec-tionrdquo Current Molecular Pharmacology vol 2 no 1 pp 95ndash1092009

[60] S Jessberger K Nakashima G D Clemenson Jr et alldquoEpigenetic modulation of seizure-induced neurogenesis andcognitive declinerdquo Journal of Neuroscience vol 27 no 22 pp5967ndash5975 2007

[61] S Yasuda M-H Liang Z Marinova A Yahyavi and D-MChuang ldquoThemood stabilizers lithiumand valproate selectivelyactivate the promoter IV of brain-derived neurotrophic factorin neuronsrdquoMolecular Psychiatry vol 14 no 1 pp 51ndash59 2009

[62] J L MacDonald and A J Roskams ldquoHistone deacetylases 1 and2 are expressed at distinct stages of neuro-glial developmentrdquoDevelopmental Dynamics vol 237 no 8 pp 2256ndash2267 2008

[63] A G Foley S Gannon N Rombach-Mullan et al ldquoClass Ihistone deacetylase inhibition ameliorates social cognition andcell adhesion molecule plasticity deficits in a rodent model ofautism spectrum disorderrdquo Neuropharmacology vol 63 no 4pp 750ndash760 2012

[64] C J Phiel F Zhang E Y Huang M G Guenther M A Lazarand P S Klein ldquoHistone deacetylase is a direct target of valproicacid a potent anticonvulsant mood stabilizer and teratogenrdquoJournal of Biological Chemistry vol 276 no 39 pp 36734ndash36741 2001

[65] O H Kramer P Zhu H P Ostendorff et al ldquoThe histonedeacetylase inhibitor valproic acid selectively induces proteaso-mal degradation of HDAC2rdquo EMBO Journal vol 22 no 13 pp3411ndash3420 2003

[66] Y Hao T Creson L Zhang et al ldquoMood stabilizer valproatepromotes ERK pathway-dependent cortical neuronal growthand neurogenesisrdquo Journal of Neuroscience vol 24 no 29 pp6590ndash6599 2004

[67] C FGeier KGarver R Terwilliger andB Luna ldquoDevelopmentof working memory maintenancerdquo Journal of Neurophysiologyvol 101 no 1 pp 84ndash99 2009

[68] G Golarai D G Ghahremani SWhitfield-Gabrieli et al ldquoDif-ferential development of high-level visual cortex correlates withcategory-specific recognition memoryrdquo Nature Neurosciencevol 10 no 4 pp 512ndash522 2007

[69] B Luna K E Garver T A Urban N A Lazar and J ASweeney ldquoMaturation of cognitive processes from late child-hood to adulthoodrdquo Child Development vol 75 no 5 pp 1357ndash1372 2004

[70] K S ScherfM Behrmann KHumphreys and B Luna ldquoVisualcategory-selectivity for faces places and objects emerges alongdifferent developmental trajectoriesrdquo Developmental Sciencevol 10 no 4 pp F15ndashF30 2007


[71] P Shaw K Eckstrand W Sharp et al ldquoAttention-deficithyperactivity disorder is characterized by a delayin cortical maturationrdquo Proceedings of the National Academyof Sciences of the United States of America vol 104 no 49 pp19649ndash19654 2007

[72] N Gogtay J N Giedd L Lusk et al ldquoDynamic mapping ofhuman cortical development during childhood through earlyadulthoodrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 101 no 21 pp 8174ndash8179 2004

[73] E I Knudsen J J Heckman J L Cameron and J P Shon-koff ldquoEconomic neurobiological and behavioral perspectiveson building Americarsquos future workforcerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 103 no 27 pp 10155ndash10162 2006

[74] J L Elman ldquoLearning and development in neural networks theimportance of starting smallrdquoCognition vol 48 no 1 pp 71ndash991993

[75] S R Quartz ldquoThe constructivist brainrdquo Trends in CognitiveSciences vol 3 no 2 pp 48ndash57 1999

[76] P Penzes M E Cahill K A Jones J Vanleeuwen and KM Woolfrey ldquoDendritic spine pathology in neuropsychiatricdisordersrdquoNature Neuroscience vol 14 no 3 pp 285ndash293 2011

[77] N Mosammaparast and Y Shi ldquoReversal of histone methy-lation biochemical and molecular mechanisms of histonedemethylasesrdquo Annual Review of Biochemistry vol 79 pp 155ndash179 2010

[78] E W Tung and L M Winn ldquoEpigenetic modifications invalproic acid-induced teratogenesisrdquo Toxicology and AppliedPharmacology vol 248 no 3 pp 201ndash209 2010

[79] A E Handel G C Ebers and S V Ramagopalan ldquoEpigeneticsmolecular mechanisms and implications for diseaserdquo Trends inMolecular Medicine vol 16 no 1 pp 7ndash16 2010

[80] R Tuchman and I Rapin ldquoEpilepsy in autismrdquo Lancet Neurol-ogy vol 1 no 6 pp 352ndash358 2002

[81] M G Chez M Chang V Krasne C Coughlan M Kominskyand A Schwartz ldquoFrequency of epileptiform EEG abnormali-ties in a sequential screening of autistic patients with no knownclinical epilepsy from 1996 to 2005rdquo Epilepsy and Behavior vol8 no 1 pp 267ndash271 2006

[82] KM Dalton BM Nacewicz T Johnstone et al ldquoGaze fixationand the neural circuitry of face processing in autismrdquo NatureNeuroscience vol 8 no 4 pp 519ndash526 2005

[83] C W Nordahl R Scholz X Yang et al ldquoIncreased rate ofamygdala growth in children aged 2 to 4 years with autismspectrum disorders a longitudinal studyrdquo Archives of GeneralPsychiatry vol 69 no 1 pp 53ndash61 2012

[84] K C Kim D K Lee H S Go et al ldquoPax6-dependent corticalglutamatergic neuronal differentiation regulates autism-likebehavior in prenatally valproic acid-exposed rat offspringrdquoMolecular Neurobiology 2013

[85] A Banerjee F Garcıa-Oscos S Roychowdhury et al ldquoImpair-ment of cortical GABAergic synaptic transmission in anenvironmental rat model of autismrdquo International Journal ofNeuropsychopharmacology vol 16 no 6 pp 1309ndash1318 2013

[86] L Q Uddin K Supekar C J Lynch et al ldquoSalience network-based classification and prediction of symptom severity inchildren with autismrdquo JAMA Psychiatry vol 70 no 8 pp 869ndash879 2013

[87] Q Chen S He X Hu et al ldquoDifferential roles of NR2A-and NR2B-containing NMDA receptors in activity-dependentbrain-derived neurotrophic factor gene regulation and limbic

epileptogenesisrdquo Journal of Neuroscience vol 27 no 3 pp 542ndash552 2007

[88] H W Horch and L C Katz ldquoBDNF release from singlecells elicits local dendritic growth in nearby neuronsrdquo NatureNeuroscience vol 5 no 11 pp 1177ndash1184 2002

[89] A K McAllister D C Lo and L C Katz ldquoNeurotrophinsregulate dendritic growth in developing visual cortexrdquo Neuronvol 15 no 4 pp 791ndash803 1995

[90] A K McAllister L C Katz and D C Lo ldquoNeurotrophin reg-ulation of cortical dendritic growth requires activityrdquo Neuronvol 17 no 6 pp 1057ndash1064 1996

[91] D K Binder S D Croll C M Gall and H E ScharfmanldquoBDNF and epilepsy too much of a good thingrdquo Trends inNeurosciences vol 24 no 1 pp 47ndash53 2001

[92] M Stamou KM Streifel P E Goines and P J Lein ldquoNeuronalconnectivity as a convergent target of gene x environmentinteractions that confer risk for autism spectrum disordersrdquoNeurotoxicology and Teratology vol 36 pp 3ndash16 2013

[93] N C Spitzer ldquoActivity-dependent neurotransmitter respecifica-tionrdquo Nature Reviews Neuroscience vol 13 no 2 pp 94ndash1062012

[94] N C Spitzer ldquoElectrical activity in early neuronal develop-mentrdquo Nature vol 444 no 7120 pp 707ndash712 2006

[95] J L Rubenstein and M M Merzenich ldquoModel of autismincreased ratio of excitationinhibition in key neural systemsrdquoGenes Brain and Behavior vol 2 no 5 pp 255ndash267 2003

[96] M Vogelauer A S Krall M A McBrian J-Y Li and SA Kurdistani ldquoStimulation of histone deacetylase activity bymetabolites of intermediary metabolismrdquo Journal of BiologicalChemistry vol 287 no 38 pp 32006ndash32016 2012

[97] P Rajendran D E Williams E Ho and R H DashwoodldquoMetabolism as a key to histone deacetylase inhibitionrdquo CriticalReviews in Biochemistry and Molecular Biology vol 46 no 3pp 181ndash199 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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OphthalmologyJournal of


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Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


study describing two sibling pairs all having FVS to variousdegrees with one having been diagnosed with infantileautism [11] A second case of a boy with FVS and ASDwas reported by Williams et al in 1997 followed up with 5more cases described by the same authors in 2001 [12 13]Several larger retrospective studies have also been publishedproviding further support that in utero VPA exposure andfetal valproate syndromemay be linked to an increased risk ofASD where for example it has been reported that the rate ofASD in the children of VPA-treated mothers may be roughlyeight times larger than that of the general population [14 1535] Nevertheless many of these studies had mentioned theneed for future study to confirm the association betweenVPAand ASD

A recently published prospective cohort study byBromleyet al [33] explored the relationship between prenatal expo-sure to anti-epileptic drugs (including VPA) and the riskof neurodevelopmental disorders such as ASD ADHD andDyspraxia They performed an 11-year study observing thephysical and cognitive development of 415 children bornto mothers with epilepsy and nonepileptic controls with afinal outcome of neurodevelopmental diagnosis by 6 yearsof age Their results showed a significant increase in therisk of neurodevelopmental disorders in those women takingVPA during pregnancy with autism being the most frequentdiagnosis The researchers also suspected a dose-dependentmechanism of VPA action but were not able to show it withsignificance in the study due to low numbers of motherstaking VPA Although this study had a fairly small cohortand a relatively early endpoint (the average age of diagnosis ofASD in theUK is 5ndash11 years of age) it was the first prospectivestudy to explore the relationship of VPA to ASD [33]

A much larger and detailed population-based study byChristensen et al [34] that focused more on ASD than otherneurodevelopmental disorders was also published this yearThe large sample (655615 children) and thorough controlof the study provide the strongest evidence to date on therelationship between VPA andASD Data were from childrenborn in Denmark from 1996 through 2006 over 14 yearsuntil the end of 2010 In their analysis they controlled forother known risk factors of ASD and potential confounderssuch as parental psychiatric disease parental age at concep-tion congenital malformations and maternal epilepsy Theydivided the outcomes as Autism SpectrumDisorder (ASD) orchildhood autism (the most severe diagnosis simply referredto as ldquoautismrdquo) and reported absolute risks over the 14 yearsand hazard ratios (HR) for each The absolute risks for allchildren studied for ASD and autism were 153 and 048respectively whereas for those exposed to VPA in uterothe risks were 442 (HR 29) and 25 (HR 52) In facteven when looking at all stratifications and controls it wasconcluded that there was a significantly increased risk ofchildren developing either ASD or autism in women takingVPA during pregnancy [34]

Accumulating epidemiological studies have shown anincreased risk of children developing a neurodevelopmentaldisorder and ASD in particular if their mothers take VPAduring pregnancy These findings should encourage a dis-cussion on the risks and benefits of the treatment during

pregnancy and provide an opportunity to explore how thischemical can alter early developing biological systems thatmay relate to ASD in animal models This may facilitatethe discovery of other VPA-like substances that may subse-quently prove to be environmental or nutritional risk factorsfor the development ofASD and these could further elucidatethe role of exogenous chemicals on ASD pathology Theauthors of the two recent papers discussed above also noted aneed to define the mechanism behind the increased risk ofASD with VPA exposure Several questions arise as to therelationship between environmental exposure to chemicalssuch asVPA in themanifestation ofASD [33 34] Christensenet al suggested several mechanisms by which VPA mayincrease the risk of ASD that need further study includinginterference in neurotransmitter function neuronal apopto-sis or plasticity histone deacetylase inhibition and disruptionof folic acid metabolism [34] Studying the effects of VPAon biological tissue will provide many avenues to explore thepossible mechanism(s) of ASD

3 Valproic Acid Rodent Model of ASD

Themodel of VPA exposure proposed by Rodier et al in 1996is one of the most frequently studied animal models of ASD[36 37] (also see [38] for review) As reviewed by Dufour-Rainfray et al this model exhibits many of the structural andbehavioural features that can be observed in ASD patients[39] For example rats exposed to VPA in utero can exhibitphysical malformations (eg ear malformations) which havebeen compared to similar abnormalities that have beenobserved in some autistic patients (eg posterior rotationof the outer ear) [39] Furthermore several independentlaboratories have also shown that prenatal VPA exposure canlead to behavioral abnormalities that are strikingly similarto those observed in autistic patients including decreasedsocial interactions and sensitivity to pain increased sensi-tivity to nonpainful stimuli repetitivestereotypic-like activ-ity increased anxiety abnormally high and longer lastingfear memories which are over-generalized and harder toextinguish and changes in specific types of pup ultrasonicvocalizations [17ndash28 30 31 39] At the cellular level recentmorphological data has also suggested that a decrease in spinedensity in forebrain structures may be a substrate for distalhypo-connectivity while the increase in dendritic lengthmight support the enhancement of local hyperconnectivity[40] As pointed out by the authors this notion is consistentwith the ldquointense worldrdquo theory of ASD which postulates amain neuropathology characterized by hyperfunctioning oflocal neural microcircuits [40ndash42]

An animal model to be considered as a relevant modelof a psychiatric condition described in humans should fitseveral criteria usually described as construct face and pre-dictive validity [43] Although the effects of VPA have beentested in rodents formany years only relatively recently it hasbeen used to model ASD in rodents for studying ASD-likebehavioural features and potential treatment interventions[1 26] Roullet et al have noted that the VPA model exhibitsboth construct and face validity [38] and recent work has













Ac Me Ac

Pol

VPA

Nucleus

Me

Cytosol




Neuronal growth



Ca++













6 Conclusion


Acknowledgments


References












































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




























Ac Me Ac

Pol

VPA

Nucleus

Me

Cytosol




Neuronal growth



Ca++













6 Conclusion


Acknowledgments


References












































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















6 Conclusion


Acknowledgments


References












































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article what we have learned about autism …

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