Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 26, Pages 10698-10712Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5772-12.2013
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Funding
- Centre National de la Recherche Scientifique
- University of Strasbourg
- Department of Biotechnology, the Government of India [BT/CSH/GIA/1752]
- Jawaharlal Nehru Centre for Advanced Scientific Research, ANR [ANR-12-MALZ-0002-01]
- Indo-French Centre for the Promotion of Advanced Research [4803-3]
- Ligue Europeenne Contre la Maladie d'Alzheimer [10702]
- Alsace Alzheimer 67
- Fondation Unistra-don Pierre Fabre
- ANR [ANR-12-MALZ-0002-01]
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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.
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