A New Neurobehavioral Model of Autism in Mice: Pre- and Postnatal Exposure to Sodium Valproate
Autism symptoms, including impairments in language development, social interactions, and motor skills, have been difficult to model in rodents. Since children exposed in utero to sodium valproate (VPA) demonstrate behavioral and neuroanatomical abnormalities similar to those seen in autism, the neurodevelopmental effects of this antiepileptic agent were examined in mice following its pre- or postnatal administration. Exposed pups were evaluated in a battery of neurodevelopmental procedures designed to assess VPA-induced retardation (wherein a behavior fails to mature on schedule), regression (wherein a behavior does mature on time but then deteriorates), or intrusions (wherein normal behaviors are overshadowed by stereotypic or self-injurious behaviors). The resulting observations were interpreted in the context of this new strategy to model autism.
Available from: Michela Servadio
- "Altogether, these findings indicate that the abnormalities in at least some cases of ASD include an injury to cranial nerve motor neurons, initiated by an insult to the developing neural tube (Rodier et al., 1996). Since this first study, prenatal exposure to VPA has become the most widely used environmentally triggered model of ASD, in both rats (Rodier et al., 1996; Markram et al., 2008) and mice (Wagner et al., 2006; Gandal et al., 2010). Despite the well-known outcomes of VPA exposure during pregnancy, the underlying mechanism is still unclear. "
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ABSTRACT: Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.
- "Furthermore, the extracellular basal levels of DA, 5-HT and NA in these brain regions were not altered by prenatal VPA exposure (Table 2). These results are in contrast to the previous observations in rats  . The discrepancy may be due to the experimental conditions: VPA was administered at embryonic day 9 in the previous studies, while it was at embryonic day 12.5 in this study. "
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ABSTRACT: Previous studies suggest that dysfunction of neurotransmitter systems is associated with the pathology of autism in humans and the disease model rodents, but the precise mechanism is not known. Rodent offspring exposed prenatally to VPA shows autism-related behavioral abnormalities. The present study examined the effect of prenatal VPA exposure on brain monoamine neurotransmitter systems in male and female mice. The prenatal VPA exposure did not affect the levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in the prefrontal cortex and striatum, while it significantly reduced methamphetamine (METH) (1.0mg/kg)-induced hyperlocomotion in male offspring. In vivo microdialysis study demonstrated that prenatal VPA exposure attenuated METH-induced increases in extracellular DA levels in the prefrontal cortex, while it did not affect those in extracellular NA and 5-HT levels. Prenatal VPA exposure also decreased METH-induced c-Fos expression in the prefrontal cortex and the mRNA levels of DA D1 and D2 receptors in the prefrontal cortex. These effects of VPA were not observed in the striatum. In contrast to male offspring, prenatal VPA exposure did not affect METH-induced increase in locomotor activity and prefrontal DA levels and the D1 and D2 receptor mRNA levels in the prefrontal cortex in female offspring. These findings suggest that prenatal VPA exposure causes hypofunction of prefrontal DA system in a sex-dependent way.
Copyright © 2015. Published by Elsevier B.V.
- "The results of the mid-air righting test in this experiment are also consistent with previous work. Postnatal exposure to valproic acid has been shown to result in regression of the previously acquired skills to perform mid-air righting (Wagner et al., 2006; Banji et al., 2011). In addition to replicating previously reported deficits in behavior for valproic acid-treated mice, this experiment provided some evidence that the Nrf2 knockout mice are more sensitive to the damaging effects of valproic acid. "
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ABSTRACT: Early exposure to valproic acid results in autism-like neural and behavioral deficits in humans and other animals through oxidative stress-induced neural damage. In the present study, valproic acid was administered to genetically altered mice lacking the Nrf2 (nuclear factor-erythroid 2 related factor 2) gene on postnatal day 14 (P14). Nrf2 is a transcription factor that induces genes that protect against oxidative stress. It was found that valproic acid-treated Nrf2 knockout mice were less active in open field activity chambers, less successful on the rotorod, and had deficits in learning and memory in the Morris water maze compared to the valproic acid-treated wild type mice. Given these results, it appears that Nrf2 knockout mice were more sensitive to the neural damage caused by valproic acid administered during early development.
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