P.112 Effects of early-life fluvoxamine exposure on social behaviours of white rats depend on the timing of its perinatal administration

Abstract

Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1–2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.