Gestational Exposure to Sodium Valproate Disrupts Fasciculation of the Mesotelencephalic Dopaminergic Tract, With a Selective Reduction of Dopaminergic Output From the Ventral Tegmental Area

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 caudateputamen. 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.

A Systematic Review of Brainstem Contributions to Autism Spectrum Disorder

“…Gestational exposure to valproic acid (VPA), a commonly used anticonvulsant, antiepileptic and mood stabilizer, results in deficits of social behavior in the offspring, modeling ASD symptoms (Dubiel and Kulesza, 2016 ; Ágota et al, 2020 ). A study compared developmental neurotoxicity when rats are exposed to VPA at E9 or E11 (Kuwagata et al, 2009 ).…”

Micromolar Valproic Acid Doses Preserve Survival and Induce Molecular Alterations in Neurodevelopmental Genes in Two Strains of Zebrafish Larvae

“…Recent studies have revealed alterations in the dopaminergic systems of mice embryonically exposed to VPA [ 25 ]. Epidemiological and animal model studies have also suggested that perinatal alterations in 5HT, either above or below typical levels, may cause social behavioral deficits resembling ASDs [ 26 ].…”

The Dopamine Hypothesis of Autism Spectrum Disorder Revisited: Current Status and Future Prospects

“…The need for novel therapeutics remains acute as knowledge of new molecular targets has yet to be translated into clinical practice [62]. However, as new insights into the dopamine signaling anomalies in ASD stem from animal models [70][71][72][73][74][75], as well as neuroimmune theoretical frameworks [13,76,77], novel treatment approaches emerge.…”

“…Given the various murine models which show a strong convergence on the midbrain dopaminergic system [70][71][72][73][74][75]93], it is tempting to speculate that this brain region is a point of junction in which diverse molecular syndromes of GPCR interactome assemble in different amounts to induce specific signaling anomalies. This assumption would fit our model which pre-dicts that the changes in the midbrain/striatal/prefrontocortical neurocircuitry should be conserved across etiologies.…”