Open access

Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model

Written By

Carmem Gottfried, Victorio Bambini-Junior, Diego Baronio, Geancarlo Zanatta, Roberta Bristot Silvestrin, Tamara Vaccaro and Rudimar Riesgo

Submitted: 04 May 2012 Published: 06 March 2013

DOI: 10.5772/54824

From the Edited Volume

Recent Advances in Autism Spectrum Disorders - Volume I

Edited by Michael Fitzgerald

Chapter metrics overview

4,588 Chapter Downloads

View Full Metrics

1. Introduction

Autism spectrum disorders (ASD) have attracted public attention by its high prevalence, elevated social cost and large impact on the family [1]. Since the first descriptions of autism made by Hans Asperger in 1938 [2] and by Leo Kanner in 1943 [3, 4], much discussion has focused in the search for the triggering points of autism and identifying risk factors has become a high priority of scientists. Nevertheless, even after almost seventy years since the first reports, the etiology of autism remains unknown and its molecular basis is not well understood. Environmental factors (such as virus, bacteria, drugs, etc.) known to increase the risk of autism have critical periods of action during embryogenesis. Congenital syndromes are found in high rates in patients with autism including somatic changes originated early in the first trimester [5].

The link between rubella and autism came from epidemic rubella in which the incidence of autism diagnosis in prenatally exposed offspring was more than 10-fold higher than normal. The study describes 243 children exposed to congenital rubella, where 25% presented mental retardation, 15% had reactive behavior and 7% was included in the autism spectrum [6].

Valproic acid (VPA) has traditionally been prescribed for epilepsy, but is increasingly used for psychiatric condition, such as bipolar disease by its modulation on GABA neurotransmission [7]. Furthermore, it has been also shown to be associated with an increased prevalence of autism. In fact, prospective and retrospective studies demonstrate that exposure to VPA during pregnancy is associated with approximately three-fold increase in the rate of major anomalies and a possible set of dysmorphic features with decreased intrauterine growth [8, 9], characteristics of Fetal Valprotate Syndrome (FVS) described in item 3. Histone deacetylase (HDAC) inhibition by VPA and changes in gene expression may explain part of the teratogenicity of this drug. In utero exposure of rodents to VPA has been proposed to induce a phenotype with behavioral characteristics reminiscent of those observed in ASD and provides a robust animal model for social cognitive impairment understanding and a potential screen for the development of novel therapeutics for this condition [10]. Other possible explanations include either the effect of VPA through the increase of fetal oxidative stress, affecting mainly the brain in comparison to other fetal organs, or its inhibitory action on the folic acid mechanism [11]. In agreement, it is possible to duplicate a number of anatomic and behavioral features characteristic of human cases by exposing rat embryos to a teratogenic agents at the time of neural tube closure [12].

Thus, in utero exposure to VPA has been used as a reliable model to increase the understanding of behavioral effects evaluated by specific tests as sociability, social preference and stereotypic behavior, also observed in human patients [9, 13, 14]. The present chapter summarizes the current knowledge on the relationship between in utero exposure to VPA in humans and in autism-like animal model phenotypes, highlighting the importance of this model to the neurobiology of autism studies.

Advertisement

2. Valproic acid

The compound VPA (Figure 1A) is a fatty acid synthesized in 1882 [15] as an analogue of valeric acid, found naturally in valerian (Valeriana officinalis), used at that time as an organic solvent. The chemical names to VPA and derivatives are shown in Table 1. Antiepileptic properties of VPA, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1962, when the French researcher Pierre Eymard in a serendipity discovery observed the anticonvulsant properties of VPA while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity [16]. He found that it prevented pentylenetetrazol-induced convulsions in rodents. Since then, it has also been used for migraine and bipolar disorder. The U.S. Food and Drug Administration (FDA) approved VPA in 1978 for the treatment of seizure disorder and in 1986 approved its enteric-coated counterpart valproate semisodium (Figure 1B) also named divalproex sodium (USA), for the same indication. Valproate semisodium is a stable co-ordination compound comprised of sodium valproate (Figure 1C) and valproic acid in a 1:1 molar relationship in an enteric coated form. An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed. This compound dissociates to release valproate ions into the gastrointestinal tract. Once in the blood, sodium valproate can be converted also in the acid form or conjugated as valproate semisodium [17]. The acid form is currently used to quantify plasma levels of all three.

Valproic Acid 2-Propylvaleric acid, 2-Propylpentanoic acid or Di-n-dipropylacetic acid
Sodium Valproate Sodium 2-propylvalerate
Valproate semisodium Sodium hydrogen bis(2-propylvalerate)
Valproate Pivoxil Hydroxymethyl 2-propylvalerate pivalate
Valpromide 2-Propylvaleramide

Table 1.

Chemical names of VPA and derivatives

Figure 1.

The molecular structure of VPA and derivatives showed in ball and stick view. A. Valproic acid. B. Valproate semisodium, C. Sodium valproate. In A is possible to compare both chemical and ball and stick structures (used also to illustrate derivatives).

The therapeutic concentration of sodium valproate (the sodium salt of VPA) during chronic oral treatment ranges from 40-100 mg/mL (280–700 mmol/L) in plasma and from 6–27 mg/g (42–190 mmol/g) in brain [18]. From this point, to simplify the reading throughout the text, the VPA abbreviation will be used when referring to valproic acid and derivatives.

The VPA is marketed under brand names including: Convulex (Pfizer-UK and Byk Madaus-South Africa), Depakene (Abbott Laboratories-USA, Brazil and Canada), Depakine (Sanofi Aventis-France and Sanofi Synthelabo-Romania), Deprakine (Sanofi Aventis-Finland), Encorate (Sun Pharmaceuticals-India), Epilim (Sanofi Synthelabo-Australia), Valcote (Abbot Laboratories-Argentina).

The VPA effects of clinical importance include GABAergic activity increase, excitatory neurotransmission decrease, and modification of monoamines [19]. The biochemical and biological effects of VPA are summarized in Table 2.

Target of action Biological effects Reference
HDAC (inhibition) Open DNA transcription [20]
Mitochondria Energy metabolism impairment [21]
Lymphocytes Modification of the epigenotype [22]
Neurons from substantia nigra Reduction in firing rate [23]
c-Jun N-terminal kinase (JNK) Defective neurite formation [24]
GSK3β inhibitor Promotion of hair re-growth [25]
Beta-catenin-Ras-ERK-p21Cip/WAF1 pathway Differentiation and inhibition of proliferation in neural progenitor cells [26]
Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) Up-regulation of CYP3A4 and MDR1 gene expression [27]
Matrix metalloprotease-9 inhibitor Attenuation of blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) [28]
PI3K/Akt/mTOR pathway Skeletal muscle hypertrophy [29]

Table 2.

Biochemical and biological effects of VPA

Advertisement

3. Valproic acid as an environmental risk factor in the development of autism

After the VPA license for use in 1978, the first adverse report of a fetus exposed to the drug was published in 1980 [30]. Since then. particular attention has been directed to the occurrence of neural tube defects in infants exposed to VPA in utero [31, 32]. The critical period for exposure to teratogens shown to increase the risk of autism is early in the first trimester [33]. Some of the critical teratogens related to autism risk are maternal rubella infection [6], ethanol [34], thalidomide [35] and VPA [8, 9]. Approximately one in 250 pregnancies is known to be exposed to antiepileptic drugs [36] and a significant proportion of these are exposed to VPA, either as monotherapy or as part of a polytherapy drug regimen.

The timing for the teratogenic effect of VPA that increases the risk for autism cannot be estimated directly, as the drug is typically taken throughout the entire pregnancy [33]. Many children exposed in utero to VPA exhibit FVS, first described in 1984 [37] and characterized by a major and minor malformations and developmental and behavioral delays [8, 12, 38-40]. Specific impairments observed in FVS includes neural tube defects, trigonocephaly, radial ray defects, pulmonary abnormalities, coloboma of iris/optic disc, low verbal IQ and features of ASD [41] and has been reported in a number of sibling pairs [12, 21, 37, 42-44] with different degree of severity among affected siblings. Common facial features of FVS include epicanthal folds, broad nasal bridge, short nose with antiverted nares, long upper lip, and low set, posteriorly rotated ears [41].

The classical autism was first reported to be one of the behavioral outcomes of VPA exposure [41] through several case reports [12, 39, 45]. The first epidemiological study with drugs as environmental risk factors of autism was described in 2000, with 57 offspring of women taking anticonvulsants (see ref [46], summarized in Tables 3 and 4).

Features % of children
Poor social interaction 53
Poor communication skills 49
Short attention span 46
Insistence on routines 44
Hand flapping 25

Table 3.

Autism features in children exposed in utero to anticonvulsants.

No of children VPA exposure in mg (weeks of gestation)
Neural tube defect 1
1
1000 (0-5), 800 (5-40)
1200 (1-17), 1500 (17-26), 2000 (26-40)
Genitourinary 1
1
5
1000 (0-40)
1000 (0-5), 800 (5-40)
1500 (0-40)
Extremities 2
1
1000 (0-40)
1500 (0-40)
Eyes 1
1
700 (0-40)
800 (0-40)
Teeth 2
1
1000 (0-40)
1700 (0-40)
Diastasis recti 1 1200 (0-40)

Table 4.

Congenital malformations in children exposed in utero to VPA

Fifty two children were ascertained through the Fetal Anticonvulsant Syndrome Association (FACS) and five were referred to the Aberdeen Medical Genetics Service (AMGS). The number of patients exposed in utero to each anticonvulsant alone was 34 (60%) to VPA, 4 (7%) to carbamazepine, 4 (7%) to phenytoin, and 15 (26%) to more than one anticonvulsant. The number of patients with behavioral problems was 46 (81%), with hyperactivity or poor concentration was 22 (39%) and with attention deficit and hyperactivity disorder 4 (7%). Autistic features were present in 34 patients (60%).

Advertisement

4. Animal model of autism induced by prenatal exposure to VPA

Considering human evidences of autism followed by early in utero exposure to teratogens, such as thalidomide and VPA, the next step was to develop a model of autism induced by prenatal exposure of animals to the same drugs, particularly VPA [47]. The in utero exposure to VPA induced patterns of abnormal development across species as demonstrated in Table 5.

Patterns of abnormal development Specie References
Skeletal abnormalities Mice [48, 49]
Rabbits [50]
Rhesus monkey [51]
Cardiac abnormalities Mice [52]
Neural tube defects (including spina bifida) Mice [53]
Cranial neural tube defects Rats [54]
Behavioral abnormalities Rats [55]

Table 5.

Patterns of abnormal development across species after in utero exposure to VPA.

The use of animal models allows a wide range of research possibilities including the search for etiologic clues, molecular targets, and biomarkers. The main aspects to take into account in developing animal models, is (i) to reproduce a circumstance that would lead to a certain condition, for example, inducing a genetic disease by manipulating a specific gene; (ii) to induce similar patterns found in the studied condition, for example, observing the same behavioral alterations found in a particular impairment; (iii) to observe if the model has similarities to a human features when exposed to certain treatment [56]. The time of induction, dosage of VPA and the way of administration in rodents are variable in the literature, as demonstrated in Table 6. It is important to observe that in rats, 600 mg/Kg VPA at 12.5 days of pregnancy is the most investigated due to similarities in the features of autism. Besides the higher number of studies describing prenatal exposure to VPA, there are some protocols reporting also postnatal exposure and behavioral features of autism [57, 58].

Embryonic Day(s) Procedure
(mg/Kg VPA)
References
Mice
9 IP (200, 400, 800) [59]
9 SC (400) [60]
9, 12.5, 14.5 IP (500) [61]
11 OA (800) [62, 63]
12, 13, 14 IP (100) [64]
12.5 IP (500) [65]
13 SC (600) [66, 67]
Rats
7, 9.5, 12, 15 IP (400) [68]
8, 9, 10, 11 OA (800) [69]
9 IP (600) [70]
9 OA (800) [71-74]
9, 11 AO (800) [75, 76]
11, 12, 13 IP (200) [77]
1.5 IP (500) [78]
1.5, 12, 12.5 IP (350) [9]
12 IP (400) [79]
12 IP (600) [80-83]
12.5 IP (600) [10, 14, 84-93]
12.5 SC (350) [94]
12.5 IP (350) [95]
12.5 IP (400, 500, 600) [77]
12.5 IP (500) [96]

Table 6.

Prenatal exposure of VPA in rodents: Time of induction and dosage

The diagnoses of autism take into account behavioral alterations in three main areas: sociability, communication and behavioral stereotypies and narrow range of interests. Therefore, a consistent animal model must show similar behavioral abnormalities, which might indicate common neural alterations.

Our group has administrated a single intraperitoneal injection of 600 mg/kg VPA in pregnant rats at the embryonic day 12.5, observing variations in social memory, and flexibility to change strategy [84]. Females were kept separate and with free access to their own litters. Somatic aspects observed during the pups' development, included body weight, ear unfolding and eye opening which were unchanged between groups. In three-chambered-apparatus test, used to observe social memory, preferences and interests, the VPA group spent less time in the presence of a stranger rat and more time in the presence of an object, indicating a reduced place preference conditioned by conspecific and an increased preference for the object, revealing sociability impairments. As adults, they showed inappropriate social approach to a stranger rat, decreased preference for social novelty, apparently normal social recognition, no spatial learning deficits and normal resistance to change on Morris water maze.

Advertisement

5. Brain alterations induced by prenatal exposure to VPA

Once prenatal exposure to VPA became a reliable tool to model autism, more brain alterations were investigated in rodents exposed to this teratogen, as summarized in Table 7.

Rodent VPA (mg/kg) Findings References
Rat 500 Altered distribution of 5-HT neurons in the dorsal raphe nucleus. [71]
350 Reduction in the number of motor neurons from hypoglossal and oculomotor nuclei. [9]
500 Reduction in the number of putative synaptic contacts in connection between layer 5 pyramidal neurons. [97]
400 Prolonged neuronal progenitor cells proliferation in embrionary period. [79]
600 Decreased number of purkinje cells, neuronal degeneration and chromatolysis. [98]
Mice 500 Reduction in the number of Parvalbumin -positive inhibitory neurons in the neocortex. [99]
500 Nissl-positive cell loss in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex. [65]

Table 7.

Brain alterations induced by in utero exposure to VPA

Behavioral outcomes started to be studied, demonstrating a number of anatomic and behavioral features characteristic of human cases by exposing rodents’ embryos to VPA at the time of neural tube closure. One of the affected structures in the brains is the cerebellum. Magnetic resonance imaging showed that patients with autism have reduced size of the cerebellum when compared to controls, displaying smaller vermal lobules VI and VII. This abnormality is probably an outcome of developmental hypoplasia and not likely shrinkage or deterioration after full development had been achieved [100]. Similar alterations were found in brains from rat model of autism induced by prenatal exposure to VPA [9]. Exposed rats showed a reduction in the number of motor neurons of the earliest-forming motor nuclei (V, XII), and had the VI th and III rd cranial nerve nuclei affected. In the same way, another work found diminished number of cells in the posterior lobe of the cerebellum [86]. In this context, cerebellar anatomy alterations in humans might be due to loss of neurons in the cranial nerve motor nuclei, as demonstrated in rats.

The amygdala is likely to be also linked to autism, due to its involvement in social-emotional behavior. Rats exposed to VPA in utero had longer lasting and harder to extinguish fear memories, which could be explained by the hyperreactivity and hyperplasticity found in the lateral amygdala [96, 101]. Another work found enhanced long-term potentiation (LTP) in the medial prefrontal cortex of rats exposed to VPA, with enhanced synaptic plasticity and short- and long-term fear memories [82].

Synaptic impairments were already described in autism, which may be related to neuroligins alterations. Neuroligins are a family of proteins which play a central role in synaptic maturation and were affected in rats after in utero exposure to VPA. Neuroligin 3 mRNA expression was decreased in the hippocampus, especially in cornu ammonis (CA1) and dentate gyrus [62].

Synaptic plasticity is influenced by brain-derived neurotrophic factor (BDNF), a factor that modulates several neurochemical parameters. High levels of BDNF have been reported in the blood of patients with autism [102]. BDNF acts through TrkB-mediated activation of various signal transduction pathways, including pathways that involve PI3K, mitogen-activated kinase (MAPK), and phospholipase C-γ [103]. Infusion of BDNF in the nucleus accumbens of aged rats restored synaptic plasticity and improved cognition [104] and some environmental factors, such social isolation, results in low levels of BDNF in the hippocampus of rats [105]. Animals exposed to VPA in utero display decreased cortical BDNF mRNA expression. It is important to notice that altered levels of the transcript will not necessarily mean an altered protein expression [63]. Diminished BDNF may lead to altered synaptic development; once it is known that this neurotrophic factor is involved in development and function of serotonergic neurons [106].

Several hypotheses have arisen to explain the social deficits in autism. One of these proposals points an alteration in opioidergic mechanisms as a likely causative of behavioral impairments in this disorder [107]. Opioid peptides are involved in stress responses and affective states, and blockage of their receptors causes dysphoria in humans. Enkephalins are part of the opioid family and are distributed in brain areas, like the striatum and the nucleus accumbens, involved in processing emotional information, anxiety and fear. Exposure to VPA reduced proenkephalin mRNA expression in both the core and shell of the nucleus accumbens and dorsal striatum of rats concomitantly to anxious-like behavior [91].

The monoamine system is also altered in patients with autism and their relatives. It was demonstrated that children with autism have increased 5-HT (serotonin) synthesis capacity when compared to children with typical development [108]. Besides, it is widely known that sleep disorders are common in autistic children [109]. Interestingly, increased levels of serotonin was found in pre-frontal cortex of rats prenatally exposed to VPA in association with disrupted sleep/awake rhythm. The elevated levels of 5-HT were found during light phase of animals’ circadian rhythm [74]. It was proved that serotonergic neurons have a silent firing rate during REM sleep [110], indicating that the sleep disturbance found in the animals may be related to increased levels of 5-HT found in their prefrontal cortex. In addition, higher levels of 5-HT were also reported in the left side of hippocampus and in blood from rats [111]. However, using the whole hippocampus, it was demonstrated 46% decrease in 5-HT levels from rats exposed to VPA in utero [70].

Recently, we observed hippocampal reactive astrogliosis in the group of rats exposed in utero to VPA (see ref [84]). After 15 postnatal days, hippocampal astrocytes were intensely immunoreactive to the astroglial marker Glial Fibrillary Acidic Protein (GFAP) (Figure 2). Astrocytes are the major cell type in the central nerve system (CNS) and provide a variety of critical supportive functions that maintain neuronal homeostasis, participating of the synapse and the glutamatergic metabolism [112]. These cells become reactive in VPA group, characterized by up-regulation of GFAP and apparently show higher number of processes than the control cells as demonstrated by the squares in A and B.

Seven Fresh-frozen post mortem tissues from individuals with autism and CSF from six living autistic patients were investigated for cytokine protein profiling [113]. This study shows an active neuroinflammatory process in the cerebral cortex, white matter, and notably in the cerebellum. Immunocytochemical studies showed marked activation of microglia and astroglia. The cytokine profiling indicated that the macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, both derived from neuroglia were the most prevalent cytokines in brain tissues. We presumed that microglia/macrophage-derived pro-inflammatory cytokines regulate the transition of astrocytes into reactive astrogliosis. Nevertheless, the mechanisms which regulate the level of astroglial cell activity in the hippocampus from VPA autism model need to be investigated.

Figure 2.

Astrocyte immunoreactive to GFAP in hippocampus from rats. A. Representative image from control group, B. Representative image from VPA group. Scale bar = 50 μm

Glutamatergic excitatory synapses are the major type of synapses in the brain and it was found that glutamate metabolism is altered in autistic CNS, particularly the glutamate receptors AMPA, NMDA and mGluR5 [114]. In agreement, rats exposed in utero to VPA show impairments in excitatory/inhibitory brain balance [78]. In this context, impairment in excitatory and inhibitory signaling during certain periods of development is proposed to be involved in the autism pathophysiology [115].

Although social impairments are one of the most important features observed in autism, patients present several other symptoms, including motor disturbances. Motor stereotypies are part of the so called autism triad of impairments, but hypotonia, motor apraxia, toe-walking, have already been reported [116]. Evaluation of motor cortex neurons of rats exposed to VPA in utero showed no changes in length or volume of either basilar or apical dendrites, but presented greater dendritic arborization in comparison with controls. This data indicates that pruning of neurons is abnormal in animals prenatally exposed to VPA [95]. Evidence suggests that the same may happen in patients with autism, since there are reports of increased brain weight in autopsy cases of autism [117]. However, the involvement of the abnormal pruning in motor cortex neurons with motor disturbances in autism deserves further investigation. Individuals with autism are more likely to present hearing deficits. In a study with a group of 199 children and adolescents, 3.5% had profound bilateral hearing loss or deafness [118].

The superior olivary complex (SOC) plays different roles in hearing. It is located within the lower brainstem and it is involved in encoding temporal features of sound and descending modulation of the cochlear nucleus and cochlea for listening in background noise. Rats exposed to VPA in utero showed reduced number of neurons and disrupted neuronal morphology in the SOC. Neuronal cell bodies were smaller and more round, indicating that these anatomical feature might have a role in the hearing difficulties that are a common in patients with autism [87]. In a study with brains of patients with autism similar morphological alterations were found, including soma size, shape and number of neurons in the SOC [119].

The cerebellum have been the focus of studies involving active and chronic neuroinflammatory process in autistic patients, demonstrating the presence of proinflammatory chemokines such as MCP-1 as well as antiinflammatory cytokines such as TGF-β1 in this brain structure. These findings support the idea that a chronic state of specific cytokine activation occurs in autism [113]. Because neuroimmune responses are influenced by the genetic background of the host, the role of neuroinflammation in the context of the genetic and other factors that determine the autism phenotype remains an important issue to be investigated.

Advertisement

6. Concluding remarks and scientific challenges

The spectrum of autism comprises a multifactorial group of disorders, with phenotypic diversity related to the symptoms and increasing prevalence. One of the major challenges of cognitive neuroscience is to understand how changes in the structural properties of the brain affect the plasticity exhibited whenever a person develops, ages, learns a new skill, make social interaction or adapts to a disease. In ASD, it is necessary studies in this field attempting to explain and understand the trigger of autism. In this context, it is not easy to find a single animal model able to captures the entire molecular and cellular alterations observed in patients with ASD.

Studies of in utero interventions in the search for animal models of autism, together with the study of potential clinical markers to ASD are innovative and may generate strategies aiming (a) the prevention of autism; (b) the construction of laboratory kits as new tools to improve and anticipate diagnosis; (c) the study of neuroglial plasticity; (d) the search for new clues to unravel the etiology of ASD. Challenged by these complexities, it is necessary to evaluate the most representative animal model to which a research group may address its questions. Considering that neuroimmune responses are influenced by the host, the role of possible neuroinflammation triggered by environmental factors in utero followed by neuroglial alterations in the litters remain an important issue to be investigated.

The present chapter summarizes findings obtained in rodents exposed in utero to VPA which present important similarities to autism features, supporting it as a valuable experimental model to study neurodevelopmental alterations induced by VPA as an environmental risk factor.

References

  1. 1. WallaceSFeinDRosanoffMDawsonGHossainSBrennanLet alA global public health strategy for autism spectrum disorders. Autism Res. 2012Jun;532117
  2. 2. AspergerHDas psychisch abnormale Kind [The psychically abnormal child]. Wien Klin Wochenschr. 1938
  3. 3. KannerLAutistic Disturbances of Affective Contact. Nervous Child. 19431943221750
  4. 4. KannerLEisenbergLEarly infantile autism, 19431955Psychiatr Res Rep Am Psychiatr Assoc. 1957 Apr(7):55-65.
  5. 5. BelloS. CAutism and environmental influences: review and commentary. Rev Environ Health. 2007Apr-Jun;22213956
  6. 6. ChessSFollow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977Mar;716981
  7. 7. HaddadP. MDasAAshfaqMWieckAA review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol. 2009May;5553951
  8. 8. ArdingerH. HAtkinJ. FBlackstonR. DElsasL. JClarrenS. KLivingstoneSet alVerification of the fetal valproate syndrome phenotype. Am J Med Genet. 1988Jan;29117185
  9. 9. RodierP. MIngramJ. LTisdaleBNelsonSRomanoJEmbryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol. 1996Jun 24;370224761
  10. 10. FoleyA. GGannonSRombach-mullanNPrendergastABarryCCassidyA. Wet alClass I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder. Neuropharmacology. 2012Sep;63475060
  11. 11. BanjiDBanjiO. JAbbagoniSHayathM. SKambamSChilukaV. LAmelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. Brain Res. 2011Sep 2;141014151
  12. 12. ChristiansonA. LCheslerNKrombergJ. GFetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol. 1994Apr;3643619
  13. 13. AlsdorfRWyszynskiD. FTeratogenicity of sodium valproate. Expert Opin Drug Saf. 2005Mar;4234553
  14. 14. SchneiderTPrzewlockiRBehavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology. 2005Jan;301809
  15. 15. BurtonB. SOn the propyl derivatives and decomposition products of ethylacetoacetate. American Chemistry Journal. 188218338595
  16. 16. MeunierHCarrazGNeunierYEymardPAimardMPharmacodynamic properties of N-dipropylacetic acid]. Therapie. 1963Mar-Apr;184358
  17. 17. PerryP. JBever-stilleK. AArndtSGundersenSCorrelation of valproate plasma concentrations and dose in bipolar affective disorder. J Clin Psychopharmacol. 2000Apr;2022779
  18. 18. SilvaM. FAiresC. CLuisP. BRuiterJ. PIjlstLDuranMet alValproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review. J Inherit Metab Dis. 2008Apr 4.
  19. 19. ChateauvieuxSMorceauFDicatoMDiederichMMolecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol. 2010
  20. 20. YildirimEZhangZUzTChenC. QManevRManevHValproate administration to mice increases histone acetylation and 5-lipoxygenase content in the hippocampus. Neurosci Lett. 2003Jul 17;34521413
  21. 21. Clayton-smithJDonnaiDFetal valproate syndrome. J Med Genet. 1995Sep;3297247
  22. 22. TremolizzoLDifrancescoJ. CRodriguez-menendezVRivaCContiEGalimbertiGet alValproate induces epigenetic modifications in lymphomonocytes from epileptic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2012Oct;3914751
  23. 23. LöscherWRohlfsARundfeldtCReduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats. Brain Res. 1995Dec;702(1-2):133-44.
  24. 24. YamauchiJToriiTKusakawaSSanbeANakamuraKTakashimaSet alThe mood stabilizer valproic acid improves defective neurite formation caused by Charcot-Marie-Tooth disease-associated mutant Rab7 through the JNK signaling pathway. J Neurosci Res. 2010Nov;8814318997
  25. 25. LeeS. HYoonJShinS. HZahoorMKimH. JParkP. Jet alValproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells. PLoS One. 2012e34152.
  26. 26. JungG. AYoonJ. YMoonB. SYangD. HKimH. YLeeS. Het alValproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-Ras-ERK-21CipWAF1 pathway. BMC Cell Biol. 2008
  27. 27. CervenyLSvecovaLAnzenbacherovaEVrzalRStaudFDvorakZet alValproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos. 2007Jul;357103241
  28. 28. LeeJ. YKimH. SChoiH. YOhT. HJuB. GYuneT. YValproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem. 2012Jun;121581829
  29. 29. GurpurP. BLiuJBurkinD. JKaufmanS. JValproic acid activates the PI3K/Akt/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy. Am J Pathol. 2009Mar;17439991008
  30. 30. DalensBRaynaudE. JGaulmeJTeratogenicity of valproic acid. J Pediatr. 1980Aug;9723323
  31. 31. MastroiacovoPBertolliniRMorandiniSSegniGMaternal epilepsy, valproate exposure, and birth defects. Lancet. 1983Dec 2431
  32. 32. RobertERosaFValproate and birth defects. Lancet. 1983Nov 12;2(8359):1142.
  33. 33. ArndtT. LStodgellC. JRodierP. MThe teratology of autism. Int J Dev Neurosci. 2005Apr-May;23(2-3):189-99.
  34. 34. NansonJ. LAutism in fetal alcohol syndrome: a report of six cases. Alcohol Clin Exp Res. 1992Jun;16355865
  35. 35. StromlandKNordinVMillerMAkerstromBGillbergCAutism in thalidomide embryopathy: a population study. Dev Med Child Neurol. 1994Apr;3643516
  36. 36. LindhoutDOmtzigtJ. GPregnancy and the risk of teratogenicity. Epilepsia. 1992Suppl 4:S418
  37. 37. DiLiberti JHFarndon PA, Dennis NR, Curry CJ. The fetal valproate syndrome. Am J Med Genet. 1984Nov;19347381
  38. 38. Bescoby-chambersNForsterPBatesGFoetal valproate syndrome and autism: additional evidence of an association’. Dev Med Child Neurol. 2001Dec;43(12):847.
  39. 39. WilliamsGKingJCunninghamMStephanMKerrBHershJ. HFetal valproate syndrome and autism: additional evidence of an association. Dev Med Child Neurol. 2001Mar;4332026
  40. 40. ChessaLIannettiPFetal valproate syndrome. Am J Med Genet. 1986Jun;2423812
  41. 41. KiniUAdabNVintenJFryerAClayton-smithJDysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes. Arch Dis Child Fetal Neonatal Ed. 2006Mar;91(2):F905
  42. 42. WinterR. MDonnaiDBurnJTuckerS. MFetal valproate syndrome: is there a recognisable phenotype? J Med Genet. 1987Nov;24116925
  43. 43. KozmaCValproic acid embryopathy: report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature. Am J Med Genet. 2001Jan 15;98216875
  44. 44. MalmHKajantieEKivirikkoSKaariainenHPeippoMSomerMValproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology. 2002Aug 27;5946303
  45. 45. WilliamsP. GHershJ. HA male with fetal valproate syndrome and autism. Dev Med Child Neurol. 1997Sep;3996324
  46. 46. MooreS. JTurnpennyPQuinnAGloverSLloydD. JMontgomeryTet alA clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000Jul;37748997
  47. 47. RodierP. MIngramJ. LTisdaleBCroogV. JLinking etiologies in humans and animal models: studies of autism. Reprod Toxicol. 1997Mar-Jun;11(2-3):417-22.
  48. 48. BrownN. AKaoJFabroSTeratogenic potential of valproic acid. Lancet. 1980Mar 22;181696601
  49. 49. BrucknerALeeY. JOSheaK. SHenneberryRC. Teratogenic effects of valproic acid and diphenylhydantoin on mouse embryos in culture. Teratology. 1983Feb;2712942
  50. 50. PetrereJ. AAndersonJ. ASakowskiRFitzgeraldJ. EDe La IglesiaF. ATeratogenesis of calcium valproate in rabbits. Teratology. 1986Dec;3432639
  51. 51. MastT. JCukierskiM. ANauHHendrickxA. GPredicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model. Toxicology. 1986May;3921119
  52. 52. SonodaTOhdoSOhbaKOkishimaTHayakawaKSodium valproate-induced cardiovascular abnormalities in the Jcl:ICR mouse fetus: peak sensitivity of gestational day and dose-dependent effect. Teratology. 1993Aug;48212732
  53. 53. EhlersKSturjeHMerkerH. JNauHValproic acid-induced spina bifida: a mouse model. Teratology. 1992Feb;45214554
  54. 54. TurnerSSuchestonM. EDe PhilipR. MPaulsonR. BTeratogenic effects on the neuroepithelium of the CD-1 mouse embryo exposed in utero to sodium valproate. Teratology. 1990Apr;41442142
  55. 55. VorheesC. VBehavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats. Psychopharmacology (Berl). 19879221739
  56. 56. CrawleyJ. NMouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 2007Oct;17444859
  57. 57. YochumC. LDowlingPReuhlK. RWagnerG. CMingXVPA-induced apoptosis and behavioral deficits in neonatal mice. Brain Res. 2008Apr 8;120312632
  58. 58. WagnerG. CReuhlK. RChehMMcraePHalladayA. KA new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate. J Autism Dev Disord. 2006Aug;36677993
  59. 59. DowningCBiersJLarsonCKimballAWrightHIshiiTet alGenetic and maternal effects on valproic acid teratogenesis in C57BL/6J and DBA/2J mice. Toxicol Sci. 2010Aug;11626329
  60. 60. TungE. WWinnL. MValproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 2011Dec;80697987
  61. 61. KataokaSTakumaKHaraYMaedaYAgoYMatsudaTAutism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol. 2011Nov 18113
  62. 62. KolozsiEMackenzieR. NRoulletF. IDecatanzaroDFosterJ. APrenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice. Neuroscience. 2009Nov 10;1634120110
  63. 63. RoulletF. IWollastonLDecatanzaroDFosterJ. ABehavioral and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience. 2010Oct 13;170251422
  64. 64. FucicAStojkovicRMiskovSZeljezicDMarkovicDGjergjaRet alTransplacental genotoxicity of antiepileptic drugs: animal model and pilot study on mother/newborn cohort. Reprod Toxicol. 2010Dec;3046138
  65. 65. HaraYMaedaYKataokaSAgoYTakumaKMatsudaTEffect of prenatal valproic acid exposure on cortical morphology in female mice. J Pharmacol Sci. 201211845436
  66. 66. GandalM. JEdgarJ. CEhrlichmanR. SMehtaMRobertsT. PSiegelS. JValidating gamma oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010Dec 15;681211006
  67. 67. Mehta MV, Gandal MJ, Siegel SJ. mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism. PLoS One. 2011;6(10):e26077.
  68. 68. KimK. CKimPGoH. SChoiC. SYangS. ICheongJ. Het alThe critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol Lett. 2011Mar 5;201213742
  69. 69. TashiroYOyabuAImuraYUchidaANaritaNNaritaMMorphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies. Int J Dev Neurosci. 2011Jun;29435964
  70. 70. Dufour-rainfrayDVourch PLe Guisquet AM, Garreau L, Ternant D, Bodard S, et al. Behavior and serotonergic disorders in rats exposed prenatally to valproate: a model for autism. Neurosci Lett. 2010Feb 5;4701559
  71. 71. MiyazakiKNaritaNNaritaMMaternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism. Int J Dev Neurosci. 2005Apr-May;23(2-3):287-97.
  72. 72. NakasatoANakataniYSekiYTsujinoNUminoMAritaHSwim stress exaggerates the hyperactive mesocortical dopamine system in a rodent model of autism. Brain Res. 2008Feb 8;119312835
  73. 73. NaritaMOyabuAImuraYKamadaNYokoyamaTTanoKet alNonexploratory movement and behavioral alterations in a thalidomide or valproic acid-induced autism model rat. Neurosci Res. 2009Jan;66126
  74. 74. TsujinoNNakataniYSekiYNakasatoANakamuraMSugawaraMet alAbnormality of circadian rhythm accompanied by an increase in frontal cortex serotonin in animal model of autism. Neurosci Res. 2007Feb;57228995
  75. 75. KuwagataMOgawaTShiodaSNagataTObservation of fetal brain in a rat valproate-induced autism model: a developmental neurotoxicity study. Int J Dev Neurosci. 2009Jun;274399405
  76. 76. OgawaTKuwagataMHoriYShiodaSValproate-induced developmental neurotoxicity is affected by maternal conditions including shipping stress and environmental change during early pregnancy. Toxicol Lett. 2007Nov 1;174(1-3):18-24.
  77. 77. DendrinosGHemeltMKellerAPrenatal VPA Exposure and Changes in Sensory Processing by the Superior Colliculus. Front Integr Neurosci. 2011
  78. 78. RinaldiTKulangaraKAntonielloKMarkramHElevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A. 2007Aug 14;10433135016
  79. 79. GoH. SChan Kim K, Choi CS, Jeon SJ, Kwon KJ, Han SH, et al. Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3beta/beta-catenin pathway. Neuropharmacology. 2012Jul 27.
  80. 80. StantonM. EPelosoEBrownK. LRodierPDiscrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism. Behav Brain Res. 2007Jan 10;176113340
  81. 81. StodgellC. JIngramJ. LOBaraMTisdaleB. KNauHRodierPM. Induction of the homeotic gene Hoxa1 through valproic acid’s teratogenic mechanism of action. Neurotoxicol Teratol. 2006Sep-Oct;28561724
  82. 82. SuiLChenMPrenatal exposure to valproic acid enhances synaptic plasticity in the medial prefrontal cortex and fear memories. Brain Res Bull. 2012Apr 10;87655663
  83. 83. MurawskiN. JBrownK. LStantonM. EInterstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism. Behav Brain Res. 2009Jan 23;1962297303
  84. 84. Bambini-juniorVRodriguesLBehrG. AMoreiraJ. CRiesgoRGottfriedCAnimal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain Res. 2011Aug 23;1408816
  85. 85. Felix-ortizA. CFeboMGestational valproate alters BOLD activation in response to complex social and primary sensory stimuli. PLoS One. 2012e37313.
  86. 86. IngramJ. LPeckhamS. MTisdaleBRodierP. MPrenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol. 2000May-Jun;22331924
  87. 87. LukoseRSchmidtEWolskiT. PJr., Murawski NJ, Kulesza RJ, Jr. Malformation of the superior olivary complex in an animal model of autism. Brain Res. 2011Jun 29;139810212
  88. 88. SchneiderTLabuzDPrzewlockiRNociceptive changes in rats after prenatal exposure to valproic acid. Pol J Pharmacol. 2001Sep-Oct;5355314
  89. 89. SchneiderTRomanABasta-kaimAKuberaMBudziszewskaBSchneiderKet alGender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology. 2008Jul;33672840
  90. 90. SchneiderTTurczakJPrzewlockiREnvironmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: issues for a therapeutic approach in autism. Neuropsychopharmacology. 2006Jan;3113646
  91. 91. SchneiderTZiolkowskaBGierykATyminskaAPrzewlockiRPrenatal exposure to valproic acid disturbs the enkephalinergic system functioning, basal hedonic tone, and emotional responses in an animal model of autism. Psychopharmacology (Berl). 2007Sep;193454755
  92. 92. WangZXuLZhuXCuiWSunYNishijoHet alDemethylation of specific Wnt/beta-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure. Anat Rec (Hoboken). 2010Nov;29311194753
  93. 93. YochumC. LBhattacharyaPPattiLMirochnitchenkoOWagnerG. CAnimal model of autism using GSTM1 knockout mice and early post-natal sodium valproate treatment. Behav Brain Res. 2010Jul 11;210220210
  94. 94. VorbrodtA. WDobrogowskaD. HKozlowskiP. BRabeATarnawskiMLeeM. HImmunogold study of effects of prenatal exposure to lipopolysaccharide and/or valproic acid on the rat blood-brain barrier vessels. J Neurocytol. 2005Dec;34643546
  95. 95. SnowW. MHartleKIvancoT. LAltered morphology of motor cortex neurons in the VPA rat model of autism. Dev Psychobiol. 2008Nov;5076339
  96. 96. MarkramKRinaldiTLa Mendola D, Sandi C, Markram H. Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology. 2008Mar;33490112
  97. 97. RinaldiTSilberbergGMarkramHHyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex. 2008Apr;18476370
  98. 98. SandhyaTSowjanyaJVeereshBBacopa monniera (L.) Wettst ameliorates behavioral alterations and oxidative markers in sodium valproate induced autism in rats. Neurochem Res. 2012May;375112131
  99. 99. GogollaNLeblancJ. JQuastK. BSudhofT. CFagioliniMHenschT. KCommon circuit defect of excitatory-inhibitory balance in mouse models of autism. J Neurodev Disord. 2009Jun;1217281
  100. 100. CourchesneEYeung-courchesneRPressG. AHesselinkJ. RJerniganT. LHypoplasia of cerebellar vermal lobules VI and VII in autism. N Engl J Med. 1988May 26;31821134954
  101. 101. MarkramHRinaldiTMarkramKThe intense world syndrome--an alternative hypothesis for autism. Front Neurosci. 2007Nov;117796
  102. 102. NelsonK. BGretherJ. KCroenL. ADambrosiaJ. MDickensB. FJelliffeL. Let alNeuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001May;495597606
  103. 103. HuangE. JReichardtL. FTrk receptors: roles in neuronal signal transduction. Annu Rev Biochem. 20037260942
  104. 104. LiMDaiF. RDuX. PYangQ. DZhangXChenYInfusion of BDNF into the nucleus accumbens of aged rats improves cognition and structural synaptic plasticity through PI3K-ILK-Akt signaling. Behav Brain Res. 2012May 16;231114653
  105. 105. ScaccianoceSDel Bianco P, Paolone G, Caprioli D, Modafferi AM, Nencini P, et al. Social isolation selectively reduces hippocampal brain-derived neurotrophic factor without altering plasma corticosterone. Behav Brain Res. 2006Apr 3;16823235
  106. 106. MartinowichKLuBInteraction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008Jan;3317383
  107. 107. ShattockPWhiteleyPBiochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002Apr;6217583
  108. 108. ChuganiD. CMuzikOBehenMRothermelRJanisseJ. JLeeJet alDevelopmental changes in brain serotonin synthesis capacity in autistic and nonautistic children. Ann Neurol. 1999Mar;45328795
  109. 109. HoshinoYWatanabeHYashimaYKanekoMKumashiroHAn investigation on sleep disturbance of autistic children. Folia Psychiatr Neurol Jpn. 19843814551
  110. 110. JacobsB. LFornalC. AActivity of brain serotonergic neurons in the behaving animal. Pharmacol Rev. 1991Dec;43456378
  111. 111. NaritaNKatoMTazoeMMiyazakiKNaritaMOkadoNIncreased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Pediatr Res. 2002Oct;5245769
  112. 112. AraqueAAstrocytes process synaptic information. Neuron Glia Biol. 2008Feb;41310
  113. 113. VargasD. LNascimbeneCKrishnanCZimmermanA. WPardoC. ANeuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005Jan;5716781
  114. 114. CarlsonG. CGlutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav. 2012Feb;10048504
  115. 115. RubensteinJ. LMerzenichM. MModel of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003Oct;2525567
  116. 116. MingXBrimacombeMWagnerG. CPrevalence of motor impairment in autism spectrum disorders. Brain Dev. 2007Oct;29956570
  117. 117. BaileyALuthertPDeanAHardingBJanotaIMontgomeryMet alA clinicopathological study of autism. Brain. 1998May;121 ( Pt 5):889-905.
  118. 118. RosenhallUNordinVSandstromMAhlsenGGillbergCAutism and hearing loss. J Autism Dev Disord. 1999Oct;29534957
  119. 119. KuleszaR. JJr., Lukose R, Stevens LV. Malformation of the human superior olive in autistic spectrum disorders. Brain Res. 2011Jan 7;136736071

Written By

Carmem Gottfried, Victorio Bambini-Junior, Diego Baronio, Geancarlo Zanatta, Roberta Bristot Silvestrin, Tamara Vaccaro and Rudimar Riesgo

Submitted: 04 May 2012 Published: 06 March 2013