title: Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue.
abstract: Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
authors.affiliation: 1] Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA [2] Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Daws
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Emin D
authors.initials: ED
authors.lastname: Ozkan
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Camilo S
authors.initials: CS
authors.lastname: Rojas
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Hubbs
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Aceti
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kilgore
authors.affiliation: The Repligen Corporation, Waltham, MA, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Kudugunti
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Sathyanarayanan V
authors.initials: SV
authors.lastname: Puthanveettil
authors.affiliation: Department of Neurobiology, The Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.affiliation: The Repligen Corporation, Waltham, MA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rusche
authors.affiliation: 1] Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA [2] Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D013569:Synapses / Q000187:drug effects*; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016708:Synaptophysin; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D006655:Histone Deacetylases
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:311-30
references.pmid: 23294310
references.citation: Nature. 2012 Mar 8;483(7388):222-6
references.pmid: 22388814
references.citation: Biol Psychiatry. 2010 Jan 1;67(1):36-43
references.pmid: 19765687
references.citation: Ann Neurol. 1991 Oct;30(4):572-80
references.pmid: 1789684
references.citation: PLoS One. 2008;3(4):e1958
references.pmid: 18463734
references.citation: Neurobiol Learn Mem. 2011 Jul;96(1):13-8
references.pmid: 21320618
references.citation: Nature. 2009 May 7;459(7243):55-60
references.pmid: 19424149
references.citation: Neuropsychopharmacology. 2013 Sep;38(10):2027-34
references.pmid: 23615664
references.citation: Mol Neurobiol. 2012 Dec;46(3):572-87
references.pmid: 22914888
references.citation: Curr Opin Pharmacol. 2008 Feb;8(1):57-64
references.pmid: 18206423
references.citation: J Neurosci. 2013 Apr 10;33(15):6401-11
references.pmid: 23575838
references.citation: Nat Chem Biol. 2006 Oct;2(10):551-8
references.pmid: 16921367
references.citation: J Biol Chem. 2004 Sep 24;279(39):40545-59
references.pmid: 15273246
references.citation: Chem Sci. 2015 Jan 1;6(1):804-815
references.pmid: 25642316
references.citation: PLoS One. 2011;6(5):e19958
references.pmid: 21625500
references.citation: J Neurosci. 2005 Jul 6;25(27):6379-88
references.pmid: 16000628
references.citation: Neuropsychopharmacology. 2010 Mar;35(4):870-80
references.pmid: 20010553
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15564-9
references.pmid: 18829438
references.citation: Nat Commun. 2011;2:510
references.pmid: 22027590
references.citation: J Neurosci. 2012 Mar 28;32(13):4651-9
references.pmid: 22457511
references.citation: Dev Dyn. 2008 Aug;237(8):2256-67
references.pmid: 18651664
references.citation: Mol Neurobiol. 2008 Feb;37(1):73-82
references.pmid: 18438727
references.citation: J Neurosci. 2011 Jan 12;31(2):764-74
references.pmid: 21228185
references.citation: Nature. 2007 May 10;447(7141):178-82
references.pmid: 17468743
references.citation: J Neurosci. 2013 Apr 10;33(15):6623-32
references.pmid: 23575859
references.citation: Neurobiol Learn Mem. 2011 Jul;96(1):41-52
references.pmid: 21545841
references.citation: Hum Mol Genet. 2012 Dec 15;21(24):5280-93
references.pmid: 22965876
references.citation: Neurobiol Learn Mem. 2014 May;111:1-8
references.pmid: 24583371
references.citation: Learn Mem. 2015 Apr;22(4):225-31
references.pmid: 25776040
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2647-52
references.pmid: 23297220
references.citation: J Neurosci. 2009 Jun 24;29(25):8288-97
references.pmid: 19553468
references.citation: Neuron. 2000 Oct;28(1):41-51
references.pmid: 11086982
references.citation: Neuron. 2011 Jun 9;70(5):813-29
references.pmid: 21658577
references.citation: J Neuropathol Exp Neurol. 2003 Dec;62(12):1220-7
references.pmid: 14692698
references.citation: Neuropharmacology. 2014 May;80:70-82
references.pmid: 24495398
references.citation: Neural Plast. 2012;2012:319836
references.pmid: 22203915
references.citation: PLoS One. 2013;8(7):e68915
references.pmid: 23894374
references.citation: Neuropharmacology. 2013 Jan;64:81-96
references.pmid: 22771460
references.citation: Neuroscience. 2013 Oct 22;251:51-65
references.pmid: 22687952
references.citation: J Mol Neurosci. 2007;31(1):47-58
references.pmid: 17416969
references.citation: Learn Mem. 2011 Jun;18(6):367-70
references.pmid: 21576516
references.citation: Neuropsychopharmacology. 2009 Jun;34(7):1721-32
references.pmid: 19145227