HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain
- PMID: 23542004
- DOI: 10.1016/j.ijdevneu.2013.03.008
HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain
Abstract
The mammalian central nervous system (CNS) undergoes significant expansion postnatally, producing astrocytes, oligodendrocytes and inhibitory neurons to modulate the activity of neural circuits. This is coincident in humans with the emergence of pediatric epilepsy, a condition commonly treated with valproate/valproic acid (VPA), a potent inhibitor of histone deacetylases (HDACs). The sequential activity of specific HDACs, however, may be essential for the differentiation of distinct subpopulations of neurons and glia. Here, we show that different subsets of CNS neural stem cells (NSCs) and progenitors switch expression of HDAC1 and HDAC2 as they commit to a neurogenic lineage in the subventricular zone (SVZ) and dentate gyrus (DG). The administration of VPA for only one week from P7-P14, combined with sequential injections of thymidine analogs reveals that VPA stimulates a significant and differential decrease in the production and differentiation of progeny of NSCs in the DG, rostral migratory stream (RMS), and olfactory bulb (OB). Cross-fostering VPA-treated mice revealed, however, that a postnatal failure to thrive induced by VPA treatment had a greater effect on DG neurogenesis than VPA action directly. By one month after VPA, OB interneuron genesis was significantly and differentially reduced in both periglomerular and granule neurons. Using neurosphere assays to test if VPA directly regulates NSC activity, we found that short term treatment with VPA in vivo reduced neurosphere numbers and size, a phenotype that was also obtained in neurospheres from control mice treated with VPA and an alternative HDAC inhibitor, Trichostatin A (TSA) at 0 and 3 days in vitro (DIV). Collectively, these data show that clinically used HDAC inhibitors like VPA and TSA can perturb postnatal neurogenesis; and their use should be carefully considered, especially in individuals whose brains are actively undergoing key postnatal time windows of development.
Keywords: BrdU; CldU; DG; DIV; HDAC inhibitors; HDACi; HDACs; IdU; NSCs; Neurogenesis; Neurospheres; OB; OE; ORN; P; RMS; SVZ; TSA; Trichostatin A; VPA; Valproic acid (valproate); bromodeoxyuridine; chlorodeoxyuridine; days in vitro; dentate gyrus; histone deacetylases; iododeoxyuridine; neural stem cells; olfactory bulb; olfactory epithelium; olfactory receptor neuron; postnatal day; rostral migratory stream; subventricular zone; valproic acid.
Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.
Similar articles
-
Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway.Eur J Pharmacol. 2014 Jan 15;723:425-30. doi: 10.1016/j.ejphar.2013.10.060. Epub 2013 Nov 7. Eur J Pharmacol. 2014. PMID: 24211784
-
Prenatal Exposure to Histone Deacetylase Inhibitors Affects Gene Expression of Autism-Related Molecules and Delays Neuronal Maturation.Neurochem Res. 2016 Oct;41(10):2574-2584. doi: 10.1007/s11064-016-1969-y. Epub 2016 Jun 14. Neurochem Res. 2016. PMID: 27300699
-
Histone deacetylase inhibitors de-repress tyrosine hydroxylase expression in the olfactory bulb and rostral migratory stream.Biochem Biophys Res Commun. 2010 Mar 19;393(4):673-7. doi: 10.1016/j.bbrc.2010.02.054. Epub 2010 Feb 17. Biochem Biophys Res Commun. 2010. PMID: 20170631 Free PMC article.
-
The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis.Cold Spring Harb Perspect Biol. 2016 May 2;8(5):a018820. doi: 10.1101/cshperspect.a018820. Cold Spring Harb Perspect Biol. 2016. PMID: 27048191 Free PMC article. Review.
-
Epigenetic control of neurotransmitter expression in olfactory bulb interneurons.Int J Dev Neurosci. 2013 Oct;31(6):415-23. doi: 10.1016/j.ijdevneu.2012.11.009. Epub 2012 Dec 3. Int J Dev Neurosci. 2013. PMID: 23220178 Free PMC article. Review.
Cited by
-
Inhibition of HDAC8 Reduces the Proliferation of Adult Neural Stem Cells in the Subventricular Zone.Int J Mol Sci. 2024 Feb 22;25(5):2540. doi: 10.3390/ijms25052540. Int J Mol Sci. 2024. PMID: 38473789 Free PMC article.
-
Radiotherapy Side Effects: Comprehensive Proteomic Study Unraveled Neural Stem Cell Degenerative Differentiation upon Ionizing Radiation.Biomolecules. 2022 Nov 26;12(12):1759. doi: 10.3390/biom12121759. Biomolecules. 2022. PMID: 36551187 Free PMC article.
-
Epigenetics of neural differentiation: Spotlight on enhancers.Front Cell Dev Biol. 2022 Oct 13;10:1001701. doi: 10.3389/fcell.2022.1001701. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 36313573 Free PMC article. Review.
-
The role of histone modifications: from neurodevelopment to neurodiseases.Signal Transduct Target Ther. 2022 Jul 6;7(1):217. doi: 10.1038/s41392-022-01078-9. Signal Transduct Target Ther. 2022. PMID: 35794091 Free PMC article. Review.
-
HDAC1 Regulates Neuronal Differentiation.Front Mol Neurosci. 2022 Jan 12;14:815808. doi: 10.3389/fnmol.2021.815808. eCollection 2021. Front Mol Neurosci. 2022. PMID: 35095417 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous