Your browser doesn't support javascript.
loading
Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue.
Rumbaugh, Gavin; Sillivan, Stephanie E; Ozkan, Emin D; Rojas, Camilo S; Hubbs, Christopher R; Aceti, Massimiliano; Kilgore, Mark; Kudugunti, Shashi; Puthanveettil, Sathyanarayanan V; Sweatt, J David; Rusche, James; Miller, Courtney A.
Afiliação
  • Rumbaugh G; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Sillivan SE; 1] Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA [2] Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
  • Ozkan ED; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Rojas CS; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Hubbs CR; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Aceti M; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Kilgore M; Department of Neurobiology, The Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • Kudugunti S; The Repligen Corporation, Waltham, MA, USA.
  • Puthanveettil SV; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
  • Sweatt JD; Department of Neurobiology, The Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • Rusche J; The Repligen Corporation, Waltham, MA, USA.
  • Miller CA; 1] Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA [2] Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
Neuropsychopharmacology ; 40(10): 2307-16, 2015 Sep.
Article em En | MEDLINE | ID: mdl-25837283
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapses / Inibidores de Histona Desacetilases / Histona Desacetilases / Transtornos da Memória Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Neuropsychopharmacology Assunto da revista: NEUROLOGIA / PSICOFARMACOLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sinapses / Inibidores de Histona Desacetilases / Histona Desacetilases / Transtornos da Memória Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Neuropsychopharmacology Assunto da revista: NEUROLOGIA / PSICOFARMACOLOGIA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos