Effects of developmental alcohol and valproic acid exposure on play behavior of ferrets

Abstract

Exposure to alcohol and valproic acid (VPA) during pregnancy can lead to fetal alcohol spectrum disorders and fetal valproate syndrome, respectively. Altered social behavior is a hallmark of both these conditions and there is ample evidence showing that developmental exposure to alcohol and VPA affect social behavior in rodents. However, results from rodent models are somewhat difficult to translate to humans owing to the substantial differences in brain development, morphology, and connectivity. Since the cortex folding pattern is closely related to its specialization and that social behavior is strongly influenced by cortical structures, here we studied the effects of developmental alcohol and VPA exposure on the play behavior of the ferret, a gyrencephalic animal known for its playful nature. Animals were injected with alcohol (3.5 g/kg, i.p.), VPA (200 mg/kg, i.p.) or saline (i.p) every other day during the brain growth spurt period, between postnatal days 10 and 30. The play behavior of pairs of the same experimental group was evaluated 3 weeks later. Both treatments induced significant behavioral differences compared to controls. Alcohol and VPA exposed ferrets played less than saline treated ones, but while animals from the alcohol group displayed a delay in start playing with each other, VPA treated ones spent most of the time close to one another without playing. These findings not only extend previous results on the effects of developmental exposure to alcohol and VPA on social behavior, but make the ferret a great model to study the underlying mechanisms of social interaction.

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

“…an animal model of ASD [36,37,40,44,57]. However, VPA exposure during early postnatal life can also induce ASD -like behavioral phenotypes in mice [35,56] and ferrets [45]. These studies indicate that VPA exposure can induce an animal model of ASD over a wide range of exposure durations, from the second trimester to infancy.…”

“…Developmental VPA exposure can induce ASD-like behavioral phenotypes, including reduced social interaction in mice [35,56], rats [36][37][38], common marmosets [57], and ferrets [45]. VPA-induced behavioral deficits might be associated with cortical dysgenesis characterized by increasing neuron numbers and cortical thickening in humans [39], mice [41,43], and rats [44].…”

“…Developmental VPA exposure is a known risk factor of ASD in humans [58]. Previous work has shown that VPA exposure during the lactation period produced an autism-like behavioral phenotype in ferret pups [45]. Therefore, we hypothesized that the current VPA exposure paradigm would produce a gyrencephalic animal model of ASD in ferrets.…”

“…This can produce ASD-like behavioral phenotypes, including reduced social interaction in rodents [35][36][37][38], and cortical dysgenesis with increasing neuron numbers and/or thickening in humans [39], mice [40][41][42][43], and rats [44]. Notably, VPA exposure during the brain growth spurt period produces ASD-like social behaviors in ferrets [45].…”

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

“…Valproic acid (VPA), a well-known antiepileptic/anticonvulsant drug, also acts as an inhibitor of histone deacetylases 1 and 2 ( Göttlicher et al, 2001 ; Phiel et al, 2001 ). 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 ).…”