General developmental health in the VPA-rat model of autism

Abstract

Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

“…Dam body mass (DBM) gain during pregnancy [(DBM21 - DBM11)/litter size] was 10.8 + 2.8 g and 10.4 + 2.1 g (p > 0.05, Student's t test) for controls and VPA, respectively. Litter size (control 12.2 + 1.7 and VPA 10.5 + 2.8; p > 0.05, Student's t test) was not different between treatments, in accordance with Favre et al [43]. The offspring exhibited good health with no physical malformations.…”

“…To confirm the low toxicity of 500 mg/kg VPA, we measured the following parameters. The reabsorption rate (percentage of dams from which a vaginal plug had been detected that did not give birth to a single pup) of the VPA group was 25%, as in Favre et al [43]. Consequently, the number of VPA dams that gave birth was 3.…”

Early physical and motor development of mouse offspring exposed to valproic acid throughout intrauterine development

“…Animal studies have been carried out in order to mimic the effects of VPA on human development [9,20]. Dose-related (150-600 mg/kg/day) teratogenicity and behavioral outcomes associated with in utero VPA exposure during the second and third weeks of intrauterine development were examined by Vorhees [21,22]; however, the early motor outcome was not accentuated.…”

“…Dose-related (150-600 mg/kg/day) teratogenicity and behavioral outcomes associated with in utero VPA exposure during the second and third weeks of intrauterine development were examined by Vorhees [21,22]; however, the early motor outcome was not accentuated. The VPA rat model for autism was developed by exposing pregnant dams on gestational days 11.5, 12 or 12.5 to a VPA dose of 350 mg/kg [23], and the use of very high doses (350-800 mg/kg) of VPA during early embryonic development (E11-E12.5) has prevailed in autism research [2,20,24]. Behavioral alterations reported in a VPA rodent model of autism were summarized in a review by Markram et al [24].…”

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

“…Animal models provide the opportunity for analyzing the developmental changes that can trigger ASD-like features [24,25]. They provide the possibility to study and manipulate biological pathways for understanding, and even preventing or reversing, the appearance of the morphological, functional, and behavioral alterations found in ASD.…”