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

• Published in: Neuroscience research Vol. 65; no. 1; pp. 35 - 43
• Main Authors: Fukuchi, Mamoru, Nii, Takuya, Ishimaru, Naoki, Minamino, Aya, Hara, Daichi, Takasaki, Ichiro, Tabuchi, Akiko, Tsuda, Masaaki
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.09.2009
• Subjects: Animals; BDNF; 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; GABA A receptor; GAD; Gene Expression Profiling; Glutamate Decarboxylase - metabolism; HDAC inhibitor; Histone acetylation; Histones - metabolism; K Cl- Cotransporters; Neurons - drug effects; Neurons - metabolism; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - metabolism; Symporters - metabolism; Up-Regulation; Valproic Acid - pharmacology; VPA; HDAC inhibitor; Histone acetylation; GAD; GABA A receptor; BDNF; VPA
• ISSN: 0168-0102; 1872-8111; 1872-8111
• DOI: 10.1016/j.neures.2009.05.002

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 α4 subunit of the GABA A receptor (GABA ARα4), 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 ARγ2, 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.