**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.


**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].

The diagnoses of autism take into account behavioral alterations in three main areas: sociabil‐ ity, 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.

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

Procedure (mg/Kg VPA)

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

**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]

**References**

http://dx.doi.org/10.5772/54824

149

learning deficits and normal resistance to change on Morris water maze.

**Table 6.** Prenatal exposure of VPA in rodents: Time of induction and dosage

**Embryonic Day(s)**

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 Valproic Acid in Autism Spectrum Disorder: From an Environmental Risk Factor to a Reliable Animal Model http://dx.doi.org/10.5772/54824 149


**Table 6.** Prenatal exposure of VPA in rodents: Time of induction and dosage

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

Skeletal abnormalities

148 Recent Advances in Autism Spectrum Disorders - Volume I

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**

Cardiac abnormalities Mice [52]

Cranial neural tube defects Rats [54] Behavioral abnormalities Rats [55]

Neural tube defects (including spina bifida) Mice [53]

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

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

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

**Table 5.** Patterns of abnormal development across species after *in utero* exposure to VPA.

reporting also postnatal exposure and behavioral features of autism [57, 58].

common neural alterations.

Mice [48, 49] Rabbits [50] Rhesus monkey [51]

> 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.
