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Pharmacological selectivity within class I histone deacetylases predicts effects on synaptic function and memory rescue

Bibliographic

Year of Publication:
2015
Contact PI Name:
Gavin Rumbaugh
Contact PI Affiliation:
Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA
Co-Authors:
Stephanie E. Sillivan, Emin D. Ozkan, Camilo S. Rojas, Christopher R. Hubbs, Massimiliano Aceti, Mark Kilgore, Shashi Kudugunti, Sathyanarayanan V. Puthanveettil, J. David Sweatt, James Rusche, Courtney A. Miller
Primary Reference (PubMED ID):
Funding Source:
National Institute on Drug Abuse (NIDA)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Mental Health (NIMH)
Study Goal and Principal Findings:

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. This study 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
RGFP966
Therapeutic Target:
Histone Deacetylase 3 (HDAC3)
Therapy Type:
Small Molecule
Therapeutic Agent:
RGFP963
Therapeutic Target:
Histone Deacetylases 1-2-3 (HDACs 1-2-3)
Therapy Type:
Small Molecule
Therapeutic Agent:
RGFP968
Therapeutic Target:
Histone Deacetylases 1-2-3 (HDACs 1-2-3)
Therapy Type:
Small Molecule
Therapeutic Agent:
RGFP233
Therapeutic Target:
Histone Deacetylase 1 (HDAC1)
Therapeutic Notes:
Histone deacetylase 1 (HDAC1) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
CD-1
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57BL/6
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Contextual Fear Conditioning
Biochemical
IC50
Target Selectivity
Immunochemistry
Synaptophysin
Microscopy
Dendritic Spine Density
Synaptogenesis
Electrophysiology
Excitatory Postsynaptic Currents
Omics
Gene Expression Profile