Can Valproic Acid Regulate Neurogenesis from Nestin+ Cells in the Adult Midbrain?

Abstract

Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms (e.g. tremor, muscle rigidity, bradykinesia, postural instability) of Parkinson's disease (PD). It is generally agreed that replacing these neurons will provide better motor symptom relief and fewer side effects than current pharmacotherapies. One potential approach to this is up-regulating endogenous DA neurogenesis in SNc. In the present study, we conducted bioinformatics analyses to identify signalling pathways that control expression of Pax6 and Msx1 genes, which have been identified as potentially important neurogenic regulators in the adult midbrain. From this Valproic acid (VPA) was identified as a regulator of these pathways, and we tested VPA for its ability to regulate midbrain neurogenesis in adult mice. VPA was infused directly into the midbrain of adult NesCreERT2/R26eYFP mice using osmotic pumps attached to implanted cannula. These mice enable permanent eYFP+ labelling of adult Nestin-expressing neural precursor cells and their progeny/ontogeny. VPA did not affect the number of eYFP+ midbrain cells, but significantly reduced the number of Pax6+, Pax6+/NeuN+, eYFP+/NeuN+ and eYFP-/NeuN+ cells. However, this reduction in NeuN expression was probably via VPA's Histone de-acetylase inhibitory properties rather than reduced neuronal differentiation by eYFP + cells. We conclude that Pax6 and Msx1 are not viable targets for regulating neurogenesis in the adult midbrain.