Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

Abstract

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces {delta}-catenin mRNA levels in cultured human neurons. {delta}-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking {delta}-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces {delta}-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced {delta}-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was reversed by elevating {delta}-catenin expression. Prenatal VPA exposure significantly reduced synaptic AMPA receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of {delta}-catenin functions. HighlightsO_LIPrenatal exposure of valproic acid (VPA) in mice significantly reduces synaptic {delta}-catenin protein and AMPA receptor levels in the pups brains. C_LIO_LIVPA treatment significantly impairs dendritic branching in cultured cortical neurons, which is reversed by increased {delta}-catenin expression. C_LIO_LIVPA exposed pups exhibit impaired communication such as ultrasonic vocalization. C_LIO_LINeuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups. C_LIO_LIThe loss of {delta}-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood. C_LI