Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid

Abstract

Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4-8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.

Effect of Prenatal Valproic Acid Exposure on Cortical Morphology in Female Mice

“…We have recently shown that male mice exposed to VPA at embryonic day 12.5 (E12.5) display ASD-like behavioral abnormalities including social interaction deficits, anxiety-like behavior, and memory deficits at 4 -8 weeks of age, and that the behavioral abnormalities are accompanied with Nissl-positive cell loss in the middle and lower layers of the prefrontal cortex and lower layers of the somatosensory cortex (5). We also found that there is a sex difference in VPA-induced social interaction deficits at 8 weeks of age (5); that is, in contrast to male offspring, female offspring did not show VPA-induced social interaction deficits.…”

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…However, the dose regimes used (either a moderate dose over consecutive days, or a single high dose of VPA) may induce physical malformations and even death of offspring [11,22,23], and thus complicate the interpretation of the results generated from "survivors" of such a toxic insult. In addition, despite evidence that the timing of a gestational exposure may influence the outcome of offspring [26], this has been largely overlooked.…”

“…Causes of GAD alteration in the VPA model: VPA may influence ASD risk in postnatal life via epigenetic mechanisms as it is a histone deacetylase inhibitor [80].…”

“…In contrast, rodents have been reported to be relatively resistant to VPA toxicity [21] and the majority of the reports that studies that link VPA exposure in pregnancy to ASD-like outcomes in rodents, have used either a moderate dose of VPA (200 mg/kg) over consecutive days, or a single high dose of VPA (500-800 mg/kg). However, these regimes can induce physical malformations and even death of offspring [11,22,23]. Specifically, the usual rate of perinatal loss before the postnatal day 6 in rats is 8.9%; but this increases to 15.6% following administration of 300 mg/kg VPA, and to 48.7% following administration of 500 mg/kg VPA [24].…”

Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism

“…Maternal exposure to VPA at the time of neural tube closure increases the risk of autism in humans [160][161][162][163] and causes autistic-like symptoms in rodents [164,165]. A single exposure to VPA in utero causes impaired social interactions, stereotypical hyperactivity and sensory/communication deficits in rodents' offspring [164][165][166][167]. Rodents prenatally exposed to VPA also show anatomical and molecular alterations similar to human autism including decreased cerebellar volume and Purkinje cell number [163,168,169], disrupted spine density and morphology [170][171][172], decreased expression of the autism-associated postsynaptic adhesion molecule Neuroligin 3 [173], and increased NR2A and NR2B NMDA receptor subunits [171].…”