Valproic acid triggers a sex-independent autism-like deficits, gut-brain axis, and neurodegenerative changes in the autism model of Wistar rats

📖 Top 50% JournalSep 4, 2025Behavioural pharmacology

Valproic acid causes autism-like problems, gut-brain changes, and brain cell damage in male and female rats

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Abstract

VPA-exposed rats of both sexes exhibited autism-like behaviors and neurodevelopmental changes.

Prenatal exposure to valproic acid (VPA) induced behaviors such as heightened anxiety, increased exploratory activity, and social deficits in both male and female offspring.
Both sexes showed impairments in spatial and recognition memory, along with depressive-like traits after VPA exposure.
Physiological assessments indicated altered gastrointestinal motility, increased brain edema, and impaired blood-brain barrier function in VPA-exposed rats.
Neuronal injury was observed in VPA-exposed rats, with no significant differences in estrogen β mRNA expression between sexes.
These findings highlight the necessity of including female subjects in preclinical studies related to autism spectrum disorder.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social interaction, communication, restricted interests, and repetitive behaviors. Its higher prevalence in males underscores the importance of understanding potential sex-specific differences. Prenatal exposure to valproic acid (VPA) is a widely used preclinical model to induce ASD-like traits in rodents; however, few studies have systematically compared neurobehavioral outcomes in both sexes. Here, we aimed to investigate sex-specific variations in developmental, behavioral, and physiological parameters in Wistar rat offspring prenatally exposed to VPA. Pregnant rats received a single intraperitoneal injection of VPA (600 mg/kg) or saline on gestational day (GD) 12.5, and offspring were assigned to four groups: control males, control females, VPA males, and females (n = 9 per group). VPA-exposed rats of both sexes exhibited autism-like behaviors, including heightened anxiety, increased exploratory activity, repetitive behaviors, social deficits, spatial and recognition memory impairments, and depressive-like traits. Physiological assessments revealed altered gastrointestinal (GIT) motility, increased brain edema, impaired blood-brain barrier (BBB) function, and neuronal injury with no sex-based difference in estrogen β (ERβ/ESR2) mRNA expression. These findings demonstrate that in utero exposure to VPA induces autism-like behaviors, developmental abnormalities, and neurodegenerative changes in both rat sexes, emphasizing the importance of including females in preclinical ASD research.

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