Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates

Abstract

Despite the substantial progress made in identifying genetic defects in autism spectrum disorder (ASD), the etiology for majority of ASD individuals remains elusive. Maternal exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug during pregnancy in human, has long been considered a risk factor to contribute to ASD susceptibility in offspring from epidemiological studies in humans. The similar exposures in murine models have provided tentative evidence to support the finding from human epidemiology. However, the apparent difference between rodent and human poses a significant challenge to extrapolate the findings from rodent models to humans. Here we report for the first time the neurodevelopmental and behavioral outcomes of maternal VPA exposure in non-human primates. Monkey offspring from the early maternal VPA exposure have significantly reduced NeuN-positive mature neurons in prefrontal cortex (PFC) and cerebellum and the Ki67-positive proliferating neuronal precursors in the cerebellar external granular layer, but increased GFAP-positive astrocytes in PFC. Transcriptome analyses revealed that maternal VPA exposure disrupted the expression of genes associated with neurodevelopment in embryonic brain in offspring. VPA-exposed juvenile offspring have variable presentations of impaired social interaction, pronounced stereotypies, and more attention on nonsocial stimuli by eye tracking analysis. Our findings in non-human primates provide the best evidence so far to support causal link between maternal VPA exposure and neurodevelopmental defects and ASD susceptibility in humans.

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

“…Animal models have linked embryonic VPA exposure to ASD-like behaviors as well as neurodevelopment defects. For example, maternal exposure of VPA has been shown to lead to autism-like behaviors and a reduction in mature neurons of the pre-frontal cortex and cerebellum of non-human primates (Zhao et al, 2019) and VPA exposure negatively affects the serotonergic system in rats as early as the progenitor cell stage (Dufour-Rainfray et al, 2010). Interestingly, the valproic acid rat model of autism also mimics the microbiome features of autism.…”

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

“…VPA is an anticonvulsant used to treat epilepsy, also used as a mood stabilizer to treat bipolar disorder, whose embryonic exposure has been associated with several instances of an increased risk for ASDs [ 1 , 2 , 3 ]. Based on these observations, studies using embryonic exposure to VPA have also been conducted in many vertebrate species to model the core signs of ASDs [ 4 , 5 , 6 , 7 , 8 ].…”

“…Several studies have analyzed social behavioral deficits in rodents prenatally exposed to VPA, describing lifelong impairments resembling the core signs of ASDs [ 9 ]. In rats, a single administration of VPA in utero induces gender-specific social behavior abnormalities, modifies sensitivity to sensory stimuli, and increases repetitive behavior and anxiety [ 4 , 5 , 6 , 10 ]. Mice exposed to prenatal VPA also show cellular and molecular phenotypes in the medial prefrontal cortex [ 11 ], the somatosensory cortex, the amygdala [ 12 ], the brain stem and the cerebellum [ 13 ].…”

Pregnancy data enable identification of relevant biomarkers and a partial prognosis of autism at birth

“…Experimental data also suggest an in-utero pathogenesis of ASD [23][24][25][26][27][28]. Thus, maternal immune activation or valproate administration are associated with ASD [24,29] and early post-natal alterations are observed in genetic forms of autism [30].…”