[P2-81] Prenatal Exposure to Valproic Acid Causes a Nonspecific Overexpression of Cell Cycle Regulatory Proteins in Murine Neural Progenitor Cells
Valproic acid (VPA), one of the first-line therapeutic agents for epilepsy, inhibits histone deacetylases (HDACs) and hence modifies gene expression profiles including cell-cycle related ones. Previous studies strongly suggest that prenatal VPA exposure increases the risks of congenital malformations and impaired higher brain function of offspring in human. We reported that prenatal VPA exposure alters the proliferation/differentiation profiles of neural progenitor cells (NPCs) in the embryonic neocortex, leading to increase of projection neurons in the superficial layers in postnatal mice (AOCCN, 2015). In the present study, we investigated the underlying mechanisms of such neocortical dysgenesis.
We orally administered pregnant CD-1 mice with VPA aqueous solution or distilled water (as controls) throughout pregnancy.
a) The total amount of acetylated histone H3 was increased by 23% in the NPCs.
b) The expression of cell cycle regulatory proteins, cyclin D1, cyclin dependent kinase (cdk) 2, cdk 4, and p27Kip1, was increased by 30–50% in the nucleus of NPCs early in neuronogenesis.
c) The number of Pax6-positive NPCs was increased in the ventricular zone of the embryonic cerebral wall by 15% in the final phase of neuronogenesis.
d) The population size of the secondary proliferative population was not affected.
Those observations suggest that the nonspecific increase of cell cycle regulatory proteins by prenatal VPA exposure disrupted the proliferation/differentiation profile of the NPCs leading to the expansion of the NPC population towards the terminal phase of neuronogenesis, possibly through the HDAC-inhibitory activity of VPA.
We orally administered pregnant CD-1 mice with VPA aqueous solution or distilled water (as controls) throughout pregnancy.
a) The total amount of acetylated histone H3 was increased by 23% in the NPCs.
b) The expression of cell cycle regulatory proteins, cyclin D1, cyclin dependent kinase (cdk) 2, cdk 4, and p27Kip1, was increased by 30–50% in the nucleus of NPCs early in neuronogenesis.
c) The number of Pax6-positive NPCs was increased in the ventricular zone of the embryonic cerebral wall by 15% in the final phase of neuronogenesis.
d) The population size of the secondary proliferative population was not affected.
Those observations suggest that the nonspecific increase of cell cycle regulatory proteins by prenatal VPA exposure disrupted the proliferation/differentiation profile of the NPCs leading to the expansion of the NPC population towards the terminal phase of neuronogenesis, possibly through the HDAC-inhibitory activity of VPA.