Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neuros...

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Autores principales:	Eric J Hill, David A Nagel, John D O'Neil, Elizabeth Torr, Elizabeth K Woehrling, Andrew Devitt, Michael D Coleman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c8ad896db4e497189058c36f0f97337
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spelling	oai:doaj.org-article:0c8ad896db4e497189058c36f0f973372021-11-18T07:52:57ZEffects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.1932-620310.1371/journal.pone.0058822https://doaj.org/article/0c8ad896db4e497189058c36f0f973372013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23527032/?tool=EBIhttps://doaj.org/toc/1932-6203Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.Eric J HillDavid A NagelJohn D O'NeilElizabeth TorrElizabeth K WoehrlingAndrew DevittMichael D ColemanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58822 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eric J Hill David A Nagel John D O'Neil Elizabeth Torr Elizabeth K Woehrling Andrew Devitt Michael D Coleman Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
description	Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.
format	article
author	Eric J Hill David A Nagel John D O'Neil Elizabeth Torr Elizabeth K Woehrling Andrew Devitt Michael D Coleman
author_facet	Eric J Hill David A Nagel John D O'Neil Elizabeth Torr Elizabeth K Woehrling Andrew Devitt Michael D Coleman
author_sort	Eric J Hill
title	Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
title_short	Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
title_full	Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
title_fullStr	Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
title_full_unstemmed	Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.
title_sort	effects of lithium and valproic acid on gene expression and phenotypic markers in an nt2 neurosphere model of neural development.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0c8ad896db4e497189058c36f0f97337
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Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development.

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