Neonatal valproic acid exposure produces altered gyrification related to increased parvalbumin-immunopositive neuron density with thickened sulcal floors

Abstract

Valproic acid (VPA) treatment is associated with autism spectrum disorder in humans, and ferrets can be used as a model to test this; so far, it is not known whether ferrets react to developmental VPA exposure with gyrencephalic abnormalities. The current study characterized gyrification abnormalities in ferrets following VPA exposure during neonatal periods, corresponding to the late stage of cortical neurogenesis as well as the early stage of sulcogyrogenesis. Ferret pups received intraperitoneal VPA injections (200 μg/g of body weight) on postnatal days (PD) 6 and 7. BrdU was administered simultaneously at the last VPA injection. Ex vivo MRI-based morphometry demonstrated significantly lower gyrification index (GI) throughout the cortex in VPA-treated ferrets (1.265 ± 0.027) than in control ferrets (1.327 ± 0.018) on PD 20, when primary sulcogyrogenesis is complete. VPA-treated ferrets showed significantly smaller sulcal-GIs in the rostral suprasylvian sulcus and splenial sulcus but a larger lateral sulcus surface area than control ferrets. The floor cortex of the inner stratum of both the rostral suprasylvian and splenial sulci and the outer stratum of the lateral sulcus showed a relatively prominent expansion. Parvalbumin-positive neuron density was significantly greater in the expanded cortical strata of sulcal floors in VPA-treated ferrets, regardless of the BrdU-labeled status. Thus, VPA exposure during the late stage of cortical neurogenesis may alter gyrification, primarily in the frontal and parietotemporal cortical divisions. Altered gyrification may thicken the outer or inner stratum of the cerebral cortex by increasing parvalbumin-positive neuron density.

The Proliferation of Dentate Gyrus Progenitors in the Ferret Hippocampus by Neonatal Exposure to Valproic Acid

“…The cerebral cortex was thickened and expanded its width at the posterior one-third when ferrets were exposed to VPA by an identical administration schedule to the current investigation ( Sawada et al, 2021 ). The substantial effect of neonatal VPA exposure on the ferret hippocampus may increase adult-type DG progenitors in the DG subgranular layer in the present study.…”

“…Prenatal and neonatal exposure to VPA induces ASD-like behavioral abnormalities in various mammalian species (Miyazaki et al, 2005;Yochum et al, 2008;Mychasiuk et al, 2012;Favre et al, 2013;Burenkova et al, 2014;Yasue et al, 2018), including ferrets (Krahe et al, 2016). These behavioral abnormalities are believed to be associated with cerebral cortical abnormalities that have been reported as the effect of developmental VPA exposure in ferrets (Sawada et al, 2021) and other mammalian species (Wood et al, 2014;Fujimura et al, 2016;Lauber et al, 2016). In contrast, prenatal and neonatal VPA exposure can alter the development of various brain regions other than the cerebral cortex.…”

“…VPA exposure to ferret infants decreased gyrification with thickened cerebral cortex at the sulcal floors (Sawada et al, 2021) that is comparable to the cortical abnormality observed in a type of human ADS (Ecker et al, 2013;Libero et al, 2014Libero et al, , 2019. Such gyrification abnormalities were involved in the excess production of cortical neurons by promoting neurogenesis or proliferation of cortical progenitors in ferrets (Sawada et al, 2021). The effect of neonatal VPA exposure, however, has not yet been evaluated in brain regions other than the cerebral cortex in gyrencephalic mammals such as ferrets.…”

“…Many studies have reported autism spectrum disorder (ASD)-like behavioral abnormalities induced by VPA exposure during prenatal and neonatal periods in various mammalian species such as mice ( Yochum et al, 2008 ; Burenkova et al, 2014 ), rats ( Miyazaki et al, 2005 ; Mychasiuk et al, 2012 ; Favre et al, 2013 ), common marmosets ( Yasue et al, 2018 ), and ferrets ( Krahe et al, 2016 ). These behavioral abnormalities are believed to be associated with cerebral cortical abnormalities caused by developmental VPA exposure ( Sabers et al, 2014 ; Wood et al, 2014 ; Fujimura et al, 2016 ; Lauber et al, 2016 ; Sawada et al, 2021 ). In contrast, prenatal and neonatal VPA exposure can alter the development of other brain regions, such as the hippocampus ( Edalatmanesh et al, 2013 ; Juliandi et al, 2015 ; Wang et al, 2016 ; Hou et al, 2018 ; Win-Shwe et al, 2018 ), cerebellum ( Hou et al, 2018 ; Mirza and Sharma, 2019 ), and amygdala ( Olexová et al, 2016 ; Wang et al, 2016 ).…”

“…Ferrets are small laboratory animals that have morphological characteristics of the brain similar to humans, not found in rodents: for example, the gyrencephalic cerebral cortex (Sawada and Watanabe, 2012;Kroenke et al, 2014) and torque asymmetry of the cerebellum (Sawada et al, 2015(Sawada et al, , 2020. VPA exposure to ferret infants decreased gyrification with thickened cerebral cortex at the sulcal floors (Sawada et al, 2021) that is comparable to the cortical abnormality observed in a type of human ADS (Ecker et al, 2013;Libero et al, 2014Libero et al, , 2019. Such gyrification abnormalities were involved in the excess production of cortical neurons by promoting neurogenesis or proliferation of cortical progenitors in ferrets (Sawada et al, 2021).…”