Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity
Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving ab...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/102663 https://orcid.org/0000-0003-1262-0592 |
| _version_ | 1826207350986375168 |
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| author | Fass, Daniel M. Reis, Surya A. Ghosh, Balaram Hennig, Krista M. Joseph, Nadine F. Zhao, Wen-Ning Nieland, Thomas J.F. Guan, Ji-Song Groves Kuhnle, Chelsea E. Tang, Weiping Barker, Douglas D. Mazitschek, Ralph Schreiber, Stuart L. Tsai, Li-Huei Haggarty, Stephen J. |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Fass, Daniel M. Reis, Surya A. Ghosh, Balaram Hennig, Krista M. Joseph, Nadine F. Zhao, Wen-Ning Nieland, Thomas J.F. Guan, Ji-Song Groves Kuhnle, Chelsea E. Tang, Weiping Barker, Douglas D. Mazitschek, Ralph Schreiber, Stuart L. Tsai, Li-Huei Haggarty, Stephen J. |
| author_sort | Fass, Daniel M. |
| collection | MIT |
| description | Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity. Using a CREB reporter gene cell line, we screened a library of small molecules structurally related to known HDAC inhibitors leading to the identification of a probe we termed crebinostat that produced robust activation of CREB-mediated transcription. Further characterization of crebinostat revealed its potent inhibition of the deacetylase activity of recombinant class I HDACs 1, 2, 3, and class IIb HDAC6, with weaker inhibition of the class I HDAC8 and no significant inhibition of the class IIa HDACs 4, 5, 7, and 9. In cultured mouse primary neurons, crebinostat potently induced acetylation of both histone H3 and histone H4 as well as enhanced the expression of the CREB target gene Egr1 (early growth response 1). Using a hippocampus-dependent, contextual fear conditioning paradigm, mice systemically administered crebinostat for a ten day time period exhibited enhanced memory. To gain insight into the molecular mechanisms of memory enhancement by HDAC inhibitors, whole genome transcriptome profiling of cultured mouse primary neurons treated with crebinostat, combined with bioinformatic analyses of CREB-target genes, was performed revealing a highly connected protein–protein interaction network reflecting modules of genes important to synaptic structure and plasticity. Consistent with these findings, crebinostat treatment increased the density of synapsin-1 punctae along dendrites in cultured neurons. Finally, crebinostat treatment of cultured mouse primary neurons was found to upregulate Bdnf (brain-derived neurotrophic factor) and Grn (granulin) and downregulate Mapt (tau) gene expression—genes implicated in aging-related cognitive decline and cognitive disorders. Taken together, these results demonstrate that crebinostat provides a novel probe to modulate chromatin-mediated neuroplasticity and further suggests that pharmacological optimization of selective of HDAC inhibitors may provide an effective therapeutic approach for human cognitive disorders. |
| first_indexed | 2024-09-23T13:47:58Z |
| format | Article |
| id | mit-1721.1/102663 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:47:58Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1026632022-10-01T17:14:42Z Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity Fass, Daniel M. Reis, Surya A. Ghosh, Balaram Hennig, Krista M. Joseph, Nadine F. Zhao, Wen-Ning Nieland, Thomas J.F. Guan, Ji-Song Groves Kuhnle, Chelsea E. Tang, Weiping Barker, Douglas D. Mazitschek, Ralph Schreiber, Stuart L. Tsai, Li-Huei Haggarty, Stephen J. Picower Institute for Learning and Memory Joseph, Nadine F. Guan, Ji-Song Tsai, Li-Huei Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity. Using a CREB reporter gene cell line, we screened a library of small molecules structurally related to known HDAC inhibitors leading to the identification of a probe we termed crebinostat that produced robust activation of CREB-mediated transcription. Further characterization of crebinostat revealed its potent inhibition of the deacetylase activity of recombinant class I HDACs 1, 2, 3, and class IIb HDAC6, with weaker inhibition of the class I HDAC8 and no significant inhibition of the class IIa HDACs 4, 5, 7, and 9. In cultured mouse primary neurons, crebinostat potently induced acetylation of both histone H3 and histone H4 as well as enhanced the expression of the CREB target gene Egr1 (early growth response 1). Using a hippocampus-dependent, contextual fear conditioning paradigm, mice systemically administered crebinostat for a ten day time period exhibited enhanced memory. To gain insight into the molecular mechanisms of memory enhancement by HDAC inhibitors, whole genome transcriptome profiling of cultured mouse primary neurons treated with crebinostat, combined with bioinformatic analyses of CREB-target genes, was performed revealing a highly connected protein–protein interaction network reflecting modules of genes important to synaptic structure and plasticity. Consistent with these findings, crebinostat treatment increased the density of synapsin-1 punctae along dendrites in cultured neurons. Finally, crebinostat treatment of cultured mouse primary neurons was found to upregulate Bdnf (brain-derived neurotrophic factor) and Grn (granulin) and downregulate Mapt (tau) gene expression—genes implicated in aging-related cognitive decline and cognitive disorders. Taken together, these results demonstrate that crebinostat provides a novel probe to modulate chromatin-mediated neuroplasticity and further suggests that pharmacological optimization of selective of HDAC inhibitors may provide an effective therapeutic approach for human cognitive disorders. National Institutes of Health (U.S.) (R01DA028301) National Institutes of Health (U.S.) (R01NS051874) Stanley Medical Research Institute Howard Hughes Medical Institute 2016-05-24T19:29:46Z 2016-05-24T19:29:46Z 2012-07 2012-06 Article http://purl.org/eprint/type/JournalArticle 00283908 http://hdl.handle.net/1721.1/102663 Fass, Daniel M., Surya A. Reis, Balaram Ghosh, Krista M. Hennig, Nadine F. Joseph, Wen-Ning Zhao, Thomas J.F. Nieland, et al. “Crebinostat: A Novel Cognitive Enhancer That Inhibits Histone Deacetylase Activity and Modulates Chromatin-Mediated Neuroplasticity.” Neuropharmacology 64 (January 2013): 81–96. https://orcid.org/0000-0003-1262-0592 en_US http://dx.doi.org/10.1016/j.neuropharm.2012.06.043 Neuropharmacology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Fass, Daniel M. Reis, Surya A. Ghosh, Balaram Hennig, Krista M. Joseph, Nadine F. Zhao, Wen-Ning Nieland, Thomas J.F. Guan, Ji-Song Groves Kuhnle, Chelsea E. Tang, Weiping Barker, Douglas D. Mazitschek, Ralph Schreiber, Stuart L. Tsai, Li-Huei Haggarty, Stephen J. Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title | Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title_full | Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title_fullStr | Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title_full_unstemmed | Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title_short | Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity |
| title_sort | crebinostat a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin mediated neuroplasticity |
| url | http://hdl.handle.net/1721.1/102663 https://orcid.org/0000-0003-1262-0592 |
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