Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions

Neurosci Res. 2009 Sep;65(1):35-43. doi: 10.1016/j.neures.2009.05.002. Epub 2009 May 20.

Abstract

Valproic acid (VPA), a drug used to treat epilepsy and bipolar mood disorder, inhibits histone deacetylase (HDAC), which is associated with the epigenetic regulation of gene expression. Using a microarray, we comprehensively examined which genes are affected by stimulating cultured rat cortical neurons with VPA, and found that the VPA-treatment markedly altered gene expression (up-regulated; 726 genes, down-regulated; 577 genes). The mRNA expression for brain-derived neurotrophic factor (BDNF) and the alpha4 subunit of the GABA(A) receptor (GABA(A)Ralpha4), known to be involved in epileptogenesis, was up-regulated, with the increase in BDNF exon I-IX mRNA expression being remarkable, whereas that for GABA(A)Rgamma2, GAD65 and 67, and the K(+)/Cl(-) co-transporter KCC2, which are responsible for the development of GABAergic inhibitory neurons, was down-regulated. The number of GAD67-positive neurons decreased upon VPA-treatment. Similar changes of up- and down-regulation were obtained by trichostatin A. VPA did not affect the intracellular Ca(2+) concentration and the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), suggesting its direct action on HDAC. The acetylation of histones H3 and H4 was increased in the promoters of up-regulated but not down-regulated genes. Thus, VPA may disrupt a balance between excitatory and inhibitory neuronal activities through its epigenetic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium Signaling
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Chromatin Immunoprecipitation
  • Down-Regulation*
  • Epigenesis, Genetic*
  • Gene Expression Profiling
  • Glutamate Decarboxylase / metabolism
  • Histones / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism
  • Symporters / metabolism
  • Up-Regulation*
  • Valproic Acid / pharmacology*

Substances

  • Brain-Derived Neurotrophic Factor
  • Histones
  • Receptors, GABA-A
  • Symporters
  • potassium-chloride symporters
  • Valproic Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2