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.
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.
Fukuchi
Mamoru
M
University of Toyama, Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences for Research, Sugitani 2630, Toyama 930-0194, Japan.
Nii
Takuya
T
Ishimaru
Naoki
N
Minamino
Aya
A
Hara
Daichi
D
Takasaki
Ichiro
I
Tabuchi
Akiko
A
Tsuda
Masaaki
M
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D015854:Up-Regulation; D014635:Valproic Acid / Q000494:pharmacology*; D000096922:K Cl- Cotransporters
D019208:Brain-Derived Neurotrophic Factor; D005968:Glutamate Decarboxylase; D006657:Histones; D011963:Receptors, GABA-A; D027981:Symporters; D014635:Valproic Acid; D000096922:K Cl- Cotransporters; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2