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Postnatal behavioral and inflammatory alterations in female pups prenatally exposed to valproic acid
Nadia Kazlauskas1, Marcos Campolongo1, Luciana Lucchina1
1Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, and Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, C1428EHA, Buenos Aires, Argentina.
Insights
Prenatal valproic acid (VPA) exposure in female mice caused postnatal behavioral and inflammatory changes, suggesting epigenetic alterations may underlie sex differences in Autism Spectrum Disorder (ASD) susceptibility.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Autism Spectrum Disorder (ASD) shows a higher incidence in males than females.
- Biological mechanisms contributing to this sex bias are not fully understood.
Purpose of the Study:
- To investigate biological mechanisms in female rodents that may explain the observed sex bias in ASD.
- To identify sex-specific effects of prenatal valproic acid (VPA) exposure, a validated Autism Spectrum Disorder mouse model.
Main Methods:
- Utilized a mouse model of prenatal VPA exposure.
- Assessed postnatal behavioral alterations, including righting reflex and acoustic startle response.
- Analyzed glial cell density (astrocytes, microglia) in key brain regions (prefrontal cortex, hippocampus, cerebellum).
- Examined histone 3 acetylation levels in the cerebellum.
Main Results:
- Female VPA-exposed pups exhibited delayed righting reflex and acoustic startle response acquisition.
- Alterations in astrocyte and microglial cell density were observed in female VPA pups between postnatal days 21 and 42.
- A decrease in histone 3 acetylation was noted in the cerebellum of female VPA pups at postnatal day 14.
- No differences in maternal behavior were detected between VPA and control groups.
Conclusions:
- Prenatal VPA exposure induces postnatal behavioral and inflammatory changes in female mice.
- Epigenetic alterations, specifically decreased histone 3 acetylation, may contribute to these observed changes.
- Findings suggest potential sex-specific biological mechanisms underlying ASD susceptibility and resilience.
Abstract:
In Autism Spectrum Disorders (ASD), a bias to a higher incidence in boys than in girls has been reported. With the aim to identify biological mechanisms acting in female animals that could underlie this bias, we used an extensively validated mouse model of ASD: the prenatal exposure to valproic acid (VPA). We found postnatal behavioral alterations in female VPA pups: a longer latency in righting reflex at postnatal day (P) 3, and a delay in the acquisition of the acoustic startle response. We also analyzed the density of glial cells in the prefrontal cortex, hippocampus and cerebellum, in VPA and control animals. Female VPA pups showed alterations in the density of astrocytes and microglial cells between P21 and P42, with specific dynamics in each brain region. We also found a decrease in histone 3 acetylation in the cerebellum of female VPA pups at P14, suggesting that the changes in glial cell density could be due to alterations in the epigenetic developmental program. Finally, no differences in maternal behavior were found. Our results show that female VPA pups exhibit behavioral and inflammatory alterations postnatally, although they have been reported to have normal levels of sociability in adulthood. With our work, we contribute to the understanding of biological mechanisms underlying different effects of VPA on male and female rodents, and we hope to help elucidate whether there are factors increasing susceptibility to ASD in boys and/or resilience in girls.
