Journal article
A Novel Activator of CBP/p300 Acetyltransferases Promotes Neurogenesis and Extends Memory Duration in Adult Mice
The Journal of neuroscience, Vol.33(26), pp.10698-10712
06/26/2013
DOI: 10.1523/JNEUROSCI.5772-12.2013
PMCID: PMC6618502
PMID: 23804093
Abstract
Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases.
Details
- Title: Subtitle
- A Novel Activator of CBP/p300 Acetyltransferases Promotes Neurogenesis and Extends Memory Duration in Adult Mice
- Creators
- Snehajyoti Chatterjee - Jawaharlal Nehru Centre for Advanced Scientific ResearchPushpak Mizar - 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, andRaphaelle Cassel - Laboratoire de Neurosciences CognitivesRomain Neidl - Laboratoire de Neurosciences CognitivesB. Ruthrotha Selvi - 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, andDalvoy Vasudevarao Mohankrishna - 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, andBhusainahalli M. Vedamurthy - 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, andAnne Schneider - Laboratoire de Neurosciences CognitivesOlivier Bousiges - Laboratoire de Neurosciences CognitivesChantal Mathis - Laboratoire de Neurosciences CognitivesJean-Christophe Cassel - Laboratoire de Neurosciences CognitivesMuthusamy Eswaramoorthy - Jawaharlal Nehru Centre for Advanced Scientific ResearchTapas K. Kundu - 1Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, andAnne-Laurence Boutillier - Laboratoire de Neurosciences Cognitives
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.33(26), pp.10698-10712
- DOI
- 10.1523/JNEUROSCI.5772-12.2013
- PMID
- 23804093
- PMCID
- PMC6618502
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Soc Neuroscience
- Number of pages
- 15
- Grant note
- ANR-12-MALZ-0002-01 / Jawaharlal Nehru Centre for Advanced Scientific Research, ANR; French National Research Agency (ANR) 4803-3 / Indo-French Centre for the Promotion of Advanced Research; French National Research Agency (ANR) ANR-12-MALZ-0002-01 / ANR; French National Research Agency (ANR) University of Strasbourg 10702 / Ligue Europeenne Contre la Maladie d'Alzheimer Alsace Alzheimer 67 Centre National de la Recherche Scientifique; Centre National de la Recherche Scientifique (CNRS) BT/CSH/GIA/1752 / Department of Biotechnology, the Government of India Fondation Unistra-don Pierre Fabre
- Language
- English
- Date published
- 06/26/2013
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984303851202771
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