Abstract
Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudate-putamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.
Highlights
Owing to the high and growing incidence of autism spectrum disorder (ASD), this highly complex neurodevelopmental syndrome has been a focus of the investigation
The diencephalic TH+ cell groups A12, A14 proved to be sexually dimorphic in the age groups we investigated, in agreement with previous reports (Arbogast and Voogt, 1991; Balan et al, 2000) and were, not considered for valproic acid (VPA) dependent effects
Nor did we find an alteration in the pattern of Nkx2.1 expression in E18.5 embryos of VPA exposed Nkx2.1Cre mothers
Summary
Owing to the high and growing incidence of autism spectrum disorder (ASD), this highly complex neurodevelopmental syndrome has been a focus of the investigation. One frequently used model in rodents that evolved in the recent decade is the administration of 2-propylpentanoic acid, a.k.a. valproic acid (VPA), a commonly used anticonvulsant, antiepileptic and mood stabilizer, to pregnant females, bringing about characteristic deficits of social behavior in the offspring, postpartum (Rodier et al, 1996; Schneider and Przewlocki, 2005; Wagner et al, 2006; for recent reviews see Roullet et al, 2013; Nicolini and Fahnestock, 2018). In utero exposure to VPA causes sociability deficits which become manifest postnatally, often in the adult animals (Kim et al, 2011; Moldrich et al, 2013; Roullet et al, 2013). The validity of embryonic exposure to VPA as a model is not restricted to mammals, as evidenced by recent studies in fish (Baronio et al, 2017; Chen et al, 2018) and birds (Nishigori et al, 2013; Sgadò et al, 2018; Lorenzi et al, 2019; Zachar et al, 2019)
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