Chemical names of VPA and derivatives
Autism spectrum disorders (ASD) have attracted public attention by its high prevalence, elevated social cost and large impact on the family . Since the first descriptions of autism made by Hans Asperger in 1938  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 .
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 .
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 . 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.
2. Valproic acid
The compound VPA (Figure 1A) is a fatty acid synthesized in 1882  as an analogue of valeric acid, found naturally in valerian (
|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|
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 . 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 . The biochemical and biological effects of VPA are summarized in Table 2.
|HDAC (inhibition)||Open DNA transcription|||
|Mitochondria||Energy metabolism impairment|||
|Lymphocytes||Modification of the epigenotype|||
||Reduction in firing rate|||
|c-Jun N-terminal kinase (JNK)||Defective neurite formation|||
|GSK3β inhibitor||Promotion of hair re-growth|||
|Beta-catenin-Ras-ERK-p21Cip/WAF1 pathway||Differentiation and inhibition of proliferation in neural progenitor cells|||
|Constitutive androstane receptor (CAR) and pregnane X receptor (PXR)||Up-regulation of
|Matrix metalloprotease-9 inhibitor||Attenuation of blood-spinal cord barrier (BSCB) after spinal cord injury (SCI)|||
|PI3K/Akt/mTOR pathway||Skeletal muscle hypertrophy|||
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 . Since then. particular attention has been directed to the occurrence of neural tube defects in infants exposed to VPA
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 . Many children exposed
The classical autism was first reported to be one of the behavioral outcomes of VPA exposure  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 , summarized in Tables 3 and 4).
|Poor social interaction||53|
|Poor communication skills||49|
|Short attention span||46|
|Insistence on routines||44|
|Neural tube defect||1
|1000 (0-5), 800 (5-40)
1200 (1-17), 1500 (17-26), 2000 (26-40)
1000 (0-5), 800 (5-40)
|Diastasis recti||1||1200 (0-40)|
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
4. Animal model of autism induced by prenatal exposure to VPA
Considering human evidences of autism followed by early
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 . 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].
|9||IP (200, 400, 800)|||
|9, 12.5, 14.5||IP (500)|||
|11||OA (800)||[62, 63]|
|12, 13, 14||IP (100)|||
|13||SC (600)||[66, 67]|
|7, 9.5, 12, 15||IP (400)|||
|8, 9, 10, 11||OA (800)|||
|9, 11||AO (800)||[75, 76]|
|11, 12, 13||IP (200)|||
|1.5, 12, 12.5||IP (350)|||
|12.5||IP (600)||[10, 14, 84-93]|
|12.5||IP (400, 500, 600)|||
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 . 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.
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.
|Rat||500||Altered distribution of 5-HT neurons in the dorsal raphe nucleus.|||
|350||Reduction in the number of motor neurons from hypoglossal and oculomotor nuclei.|||
|500||Reduction in the number of putative synaptic contacts in connection between layer 5 pyramidal neurons.|||
|400||Prolonged neuronal progenitor cells proliferation in embrionary period.|||
|600||Decreased number of purkinje cells, neuronal degeneration and chromatolysis.|||
|Mice||500||Reduction in the number of Parvalbumin -positive inhibitory neurons in the neocortex.|||
|500||Nissl-positive cell loss in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex.|||
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 . Similar alterations were found in brains from rat model of autism induced by prenatal exposure to VPA . 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 . 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
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
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 . BDNF acts through TrkB-mediated activation of various signal transduction pathways, including pathways that involve PI3K, mitogen-activated kinase (MAPK), and phospholipase C-γ . Infusion of BDNF in the nucleus
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 . 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
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 . Besides, it is widely known that sleep disorders are common in autistic children . 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 . It was proved that serotonergic neurons have a silent firing rate during REM sleep , 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 . However, using the whole hippocampus, it was demonstrated 46% decrease in 5-HT levels from rats exposed to VPA
Recently, we observed hippocampal reactive astrogliosis in the group of rats exposed
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 . In agreement, rats exposed
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 . Evaluation of motor cortex neurons of rats exposed to VPA
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
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 . 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.
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.
The present chapter summarizes findings obtained in rodents exposed
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