Effect of Prenatal Valproic Acid Exposure on Cortical Morphology in Female Mice

Abstract

Abstract.We have recently shown that prenatal valproic acid (VPA) exposure causes autism spectrum disorders-like behavioral abnormalities and Nissl-positive cell loss in both prefrontal and somatosensory cortices in male mice. We have also found that VPA-induced social interaction deficits are observed in male but not female offspring. This study demonstrated that the exposure to VPA at embryonic day 12.5 significantly decreased Nissl-positive cell numbers in the prefrontal cortex, but not in the somatosensory cortex, in female offspring. These findings suggest that VPAinduced morphological abnormalities in the somatosensory cortex may be involved in the sex-dependent social interaction deficits.

Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex

“…Cells with dense staining of more than half the nucleus were considered BrdUpositive (Costa et al, 2001). Somatosensory cortex was chosen based on its well-characterized architecture and evidence of susceptibility to prenatal and perinatal insult (e.g., Erzurumlu and Gaspar, 2012;Hara et al, 2012). Neuronal distributions and laminar measurements[ 9 _ T D $ D I F F ] were analyzed using a two-way ANOVA followed by a Holm-Sidak post hoc test for multiple comparisons (e.g., Poluch et al, 2008).…”

Comment on “Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring”

“…The VPA rats were extensively analyzed, and most of the autistic-like features, including sociability deficits, were not detected in females (10,11). In fact, VPA female rats are sometimes used in comparison to males to determine gender-specific alterations, which are likely to be more relevant to autism pathophysiology (11,12). In addition, there is no complete characterization of autistic-like features in female FRX mice, because the vast majority of researchers use only males in their experiments (13)(14)(15).…”

Using a mouse model to investigate male bias in autism spectrum disorder incidence.

“…Mice also display sex-dependent morphological changes, with both sexes showing decreased Nissl-positive cell numbers in the prefrontal cortex, but only males displaying cell loss in the somatosensory cortex following VPA exposure (Hara et al, 2012). In a series of neurodevelopmental tests, mice exposed to VPA displayed timing differences in development compared to controls, with sex differences observed in mid-air righting, hanging wire grip strength, water maze, and motor activity (Wagner, Reuhl, Cheh, McRae, & Halladay, 2006).…”

“…In addition, VPA treatment in rodents is associated with decreased cerebellar volume and Purkinje cell number (Ingram et al, 2000), reductions in neuroligin 3 mRNA (Kolozsi et al, 2009) and brain-derived neurotrophic factor (BDNF) mRNA expression (Roullet et al, 2010), and increased corticosterone levels and diminished immunological activity (Schneider et al, 2008). Sex differences in postnatal behavior and neural development have been reported in VPA treated rodents, wherein males display reduced nociception reactivity, heightened anxiety, social interaction deficits (Kataoka et al, 2013;Schneider et al, 2008), delayed motor development (Wagner et al, 2006), and cell loss in the somatosensory cortex (Hara et al, 2012).…”

“…Pregnant dams were injected with either 500 mg/kg VPA in saline (i.p.) or vehicle alone (Veh1) on day E12.5 (Hara et al, 2012;Kataoka et al, 2013). Fourteen pregnant dams were separated across 3 cohorts; cohort 1 had only 3 pregnant dams due to VPA litter resorption, cohort 2 had 6 dams, and cohort 3 had 5 dams.…”