Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells

• Published in: Experimental brain research 2007-02, Vol.176 (4), p.672-678
• Main Authors: SIEBZEHNRUBL, Florian A, BUSLEI, Rolf, EYUPOGLU, Ilker Y, SEUFERT, Sebastian, HAHNEN, Eric, BLUMCKE, Ingmar
• Format: Article
• Language: English
• Subjects: Age Factors; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological and medical sciences; Biomarkers - metabolism; Cell cycle; Cell death; Cell differentiation; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Proliferation - drug effects; Cells, Cultured; Chromatin; Cyclin D2; Dopamine - metabolism; Dopamine D2 receptors; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Enzymes; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenetics; Forebrain; Fundamental and applied biological sciences. Psychology; gamma-Aminobutyric Acid - metabolism; Gene expression; Histone deacetylase; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Hydroxamic acid; Isolated neuron and nerve. Neuroglia; Lymphocytes B; Motor control and motor pathways. Reflexes. Control centers of vegetative functions. Vestibular system and equilibration; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; NeuroD protein; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - enzymology; Neurospheres; Olig2 protein; Oligodendrocyte Transcription Factor 2; Oligodendrocytes; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Prosencephalon - cytology; Prosencephalon - drug effects; Prosencephalon - enzymology; Rats; Rats, Wistar; Spheres; Spheroids, Cellular; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; Stem Cells - enzymology; Subventricular zone; Tubulin; Tubulin - drug effects; Tubulin - metabolism; Vertebrates: nervous system and sense organs; γ-Aminobutyric acid
• ISSN: 0014-4819; 1432-1106
• DOI: 10.1007/s00221-006-0831-x

Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of betaIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors.