Prenatal Exposure to Histone Deacetylase Inhibitors Affects Gene Expression of Autism-Related Molecules and Delays Neuronal Maturation

Abstract

Valproic acid (VPA) is a multi-target drug and an inhibitor of histone deacetylase (HDAC). We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5), but not at E14.5, causes autism-like behavioral abnormalities in male mouse offspring. We have also found that prenatal VPA exposure causes transient histone hyperacetylation in the embryonic brain, followed by decreased neuronal cell numbers in the prefrontal and somatosensory cortices after birth. In the present study, we examined whether prenatal HDAC inhibition affects neuronal maturation in primary mouse cortical neurons. Pregnant mice were injected intraperitoneally with VPA (500 mg/kg) and the more selective HDAC inhibitor trichostatin A (TSA; 500 µg/kg) at E12.5 or E14.5, and primary neuronal cultures were prepared from the cerebral cortices of their embryos. Prenatal exposure to VPA at E12.5, but not at E14.5, decreased total number, total length, and complexity of neuronal dendrites at 14 days in vitro (DIV). The effects of VPA weakened at 21 DIV. Exposure to TSA at E12.5, but not at E14.5, also delayed maturation of cortical neurons. In addition, real-time quantitative PCR revealed that the prenatal exposure to TSA decreased neuroligin-1 (Nlgn1), Shank2, and Shank3 mRNA levels and increased contactin-associated protein-like 2 mRNA level. The delay in neuronal maturation was also observed in Nlgn1-knockdown cells, which were transfected with Nlgn1 siRNA. These findings suggest that prenatal HDAC inhibition causes changes in gene expression of autism-related molecules linked to a delay of neuronal maturation.

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

“…Although VPA is a commonly used antiepileptic drug worldwide, its toxicity and teratogenicity is a relevant problem especially in the treatment of women at childbearing age [35]. Prenatal VPA exposure of neuronal cultures from the cerebral cortices of prenatal mice embryos was shown to decrease the total number, total length, and complexity of neuronal dendrites [36]. Similarly, results obtained by Semmler et al [37] indicated that intrauterine VPA exposure caused dose-dependent neuronal cell number alterations in the hippocampal areas CA1/2 and the CA3 region and in folic acid metabolism in a rat model of valproate teratogenicity.…”

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

“…Valproate, a well-known HDAC inhibitor drug, induces important delays in neuronal maturation [34], already described in ASD [35]. Moreover, VPA prenatal exposure alters the postnatal histone 3 (H3) acetylation levels in the cerebellum [36], stimulates glial cell proliferation in the developing rat brain [37], and also induces changes in acetylation levels in the astrocytes of the hippocampus and cortex in cell culture more than other antidepressants and mood stabilizers do [38].…”

Sexually Dimorphic Epigenetic Regulation of Brain-Derived Neurotrophic Factor in Fetal Brain in the Valproic Acid Model of Autism Spectrum Disorder

“…However, VPA exposure alters expression of a wide range of genes in addition to Bdnf , including some that could dysregulate brain development and function if overexpressed in the fetal brain [68]. The results reported here show that, following in utero VPA exposure, there is more Ex1- and Ex4- Bdnf mRNA in female than in male fetal brains.…”