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CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

Abstract
The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.
AuthorsDavid Tsui, Anastassia Voronova, Denis Gallagher, David R Kaplan, Freda D Miller, Jing Wang
JournalDevelopmental biology (Dev Biol) Vol. 385 Issue 2 Pg. 230-41 (Jan 15 2014) ISSN: 1095-564X [Electronic] United States
PMID24247009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 Published by Elsevier Inc.
Chemical References
  • p300-CBP Transcription Factors
Topics
  • Animals
  • Cell Differentiation (physiology)
  • Haploinsufficiency
  • Interneurons (cytology)
  • Mice
  • Polymerase Chain Reaction
  • Prosencephalon (cytology, embryology)
  • p300-CBP Transcription Factors (genetics, physiology)

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