Prenatal stress shapes astroglial marker expression across developmental stages in rats

Background: Early-life stress, particularly prenatal stress (PNS), is associated with an increased risk of psychiatric disorders such as depression, anxiety, and schizophrenia. Its effects on brain development involve not only neuronal circuits but also glial cells, which contribute to neuroinflammation, synaptic regulation, and myelination. Astrocytes, in particular, are highly responsive to environmental changes during development and may undergo lasting functional alterations following early stress exposure. Although several studies suggest that early-life stress influences glial function, findings across rodent models remain variable, likely due to differences in experimental design, timing of exposure, sex, and brain regions analyzed. In this study, we examined how PNS affects astroglial markers across development, from fetal stages to adulthood, with a focus on sex- and region-specific patterns and their progression over time.

Methods: Pregnant Sprague–Dawley rats were exposed to repeated restraint stress during the final week of gestation. Brain tissue was collected from independent cohorts at late gestation (one day prior to delivery), postnatal day 1 (P1), adolescence (P48), and adulthood (P90). The prefrontal cortex (PFC) and ventral hippocampus (vH) were dissected and snap-frozen. RNA was extracted for transcriptomic analyses, supported by imaging-based approaches. Statistical analyses were performed using appropriate tests (One-way or Two-way ANOVA) with corrections for multiple comparisons where necessary.

Results: Prenatal stress was associated with age- and sex-dependent changes in astroglial markers. In the fetal brain, AQP4 (Aquaporin-4) expression was increased in males, while no changes were observed in females (p>0.05); SPARCL1 (SPARC-like 1) was not significantly affected (p>0.05). At P1, both AQP4 and SPARCL1 were reduced in PNS animals, with effects more evident in males. During adolescence, GFAP (Glial Fibrillary Acidic Protein) expression in the PFC was unchanged in both sexes (p>0.05), whereas in the ventral hippocampus it was reduced in PNS animals. AQP4 expression decreased specifically in the vH of female PNS rats. SPARCL1 expression was reduced in the PFC of males and in the vH of both sexes. In adulthood, GFAP expression in the PFC showed a sex-dependent pattern, decreasing in males and increasing in females following PNS, while no changes were observed in the vH (p>0.05). SPARCL1 expression was not significantly altered at this stage (p>0.05).

Conclusions: These findings suggest that the effects of prenatal stress on astroglial markers vary across development rather than remaining constant. The changes differ between males and females, with earlier alterations in males and more distinct patterns emerging in adulthood. Regional sensitivity also appears to shift over time, with the ventral hippocampus more affected during adolescence and the prefrontal cortex in adulthood. Some changes are transient, while others persist, indicating a combination of short- and longer-term effects. Overall, early-life stress appears to influence astroglial function over time, potentially shaping later cellular responses and contributing to vulnerability to psychiatric conditions.

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