Social deficits in mice prenatally exposed to valproic acid are intergenerationally inherited and rescued by social enrichment

Zappala, Cecilia; Barrios, Claudio Darío; Depino, Amaicha Mara

doi:10.1016/j.neuro.2023.05.009

Cited by 7 publications

(8 citation statements)

References 44 publications

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“…Interestingly, basal c-Fos immunoreactivity in the arcuate nucleus of VPA-exposed pups in the nest was significantly higher compared to saline-exposed animals ( Fig. 5 and Table 2 ), which is consistent with the previous findings (Campolongo et al, 2018; Dubiel & Kulesza, 2016; Zappala et al, 2023). However, a 90 min isolation was unable to further elevate c-Fos immunoreactivity in the arcuate nucleus of VPA-exposed mice compared to nest control animals ( Fig.…”

Section: Resultssupporting

confidence: 91%

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

Roh,

Mendez-Vazquez,

Sathler

et al. 2023

Preprint

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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 δ-catenin mRNA levels in cultured human neurons. δ-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 δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was reversed by elevating δ-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 δ-catenin functions.HighlightsPrenatal exposure of valproic acid (VPA) in mice significantly reduces synaptic δ-catenin protein and AMPA receptor levels in the pups’ brains.VPA treatment significantly impairs dendritic branching in cultured cortical neurons, which is reversed by increased δ-catenin expression.VPA exposed pups exhibit impaired communication such as ultrasonic vocalization.Neuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups.The loss of δ-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood.

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Section: Resultssupporting

confidence: 91%

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

Roh,

Mendez-Vazquez,

Sathler

et al. 2023

Preprint

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“…Rodent studies have reported protective and reorganizational effects on the Purkinje cell layer in response to EE, including increased dendritic tree size and the number of mature synapses in the cerebellum [61]. This protective effect may be associated with increased neuroplasticity, induced by constant sensory stimulation, contributing to changes in cellular morphology and synaptic populations [61][62][63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

Flores-Prieto,

Caycho-Salazar,

Manzo

et al. 2024

NeuroSci

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The etiology of autism spectrum disorder (ASD) has been linked to both genetic and epigenetic factors. Among the epigenetic factors, exposure to valproic acid (VPA), an antiepileptic and mood-modulating drug, has been shown to induce characteristic traits of ASD when exposed to during embryogenesis. Conversely, in animal models, enriched environment (EE) has demonstrated positive behavioral and neural effects, suggesting its potential as a complementary treatment to pharmacological approaches in central nervous system disorders. In this study, we utilized zebrafish to model ASD characteristics induced by VPA and hypothesized that sensory stimulation through EE could ameliorate the behavioral and neuroanatomical features associated with ASD. To test this hypothesis, we assessed social behavior, cerebellar volume, and Purkinje cell populations via histology and immunohistochemistry after exposing the fish to EE. The results revealed that zebrafish exposed to VPA exhibited social deficits, reduced cerebellar cortex volume, and a decrease in c-Fos-positive cells in the Purkinje layer. In contrast, VPA-exposed fish treated with EE showed increased socialization, augmented cerebellar cortex volume, and an elevation in c-Fos-positive Purkinje cells. These findings suggest that alterations induced by VPA may be ameliorated through EE treatment, highlighting the potential therapeutic impact of sensory stimulation in conditions related to ASD.

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“…The social interaction test was conducted according to established protocols 7 , 26 , 50 . Briefly, animals were habituated for 5 min to a three-chamber cage (45 cm × 15 cm) containing a Plexiglas tube in each lateral chamber.…”

Section: Methodsmentioning

confidence: 99%

“…The self-grooming test was conducted as previously described 26 , 50 . Animals were habituated to being enclosed in a 5.5-cm diameter and 20-cm high Plexiglas tube during two 60-min sessions on consecutive days.…”

Section: Methodsmentioning

confidence: 99%

Juvenile peripheral LPS exposure overrides female resilience to prenatal VPA effects on adult sociability in mice

Seiffe,

Kazlauskas,

Campolongo

et al. 2024

Sci Rep

Self Cite

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Autism spectrum disorder (ASD) exhibits a gender bias, with boys more frequently affected than girls. Similarly, in mouse models induced by prenatal exposure to valproic acid (VPA), males typically display reduced sociability, while females are less affected. Although both males and females exhibit VPA effects on neuroinflammatory parameters, these effects are sex-specific. Notably, females exposed to VPA show increased microglia and astrocyte density during the juvenile period. We hypothesized that these distinct neuroinflammatory patterns contribute to the resilience of females to VPA. To investigate this hypothesis, we treated juvenile animals with intraperitoneal bacterial lipopolysaccharides (LPS), a treatment known to elicit brain neuroinflammation. We thus evaluated the impact of juvenile LPS-induced inflammation on adult sociability and neuroinflammation in female mice prenatally exposed to VPA. Our results demonstrate that VPA-LPS females exhibit social deficits in adulthood, overriding the resilience observed in VPA-saline littermates. Repetitive behavior and anxiety levels were not affected by either treatment. We also evaluated whether the effect on sociability was accompanied by heightened neuroinflammation in the cerebellum and hippocampus. Surprisingly, we observed reduced astrocyte and microglia density in the cerebellum of VPA-LPS animals. These findings shed light on the complex interactions between prenatal insults, juvenile inflammatory stimuli, and sex-specific vulnerability in ASD-related social deficits, providing insights into potential therapeutic interventions for ASD.

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Social deficits in mice prenatally exposed to valproic acid are intergenerationally inherited and rescued by social enrichment

Cited by 7 publications

References 44 publications

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

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

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

Juvenile peripheral LPS exposure overrides female resilience to prenatal VPA effects on adult sociability in mice

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