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.

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013). These differences may be because of the selectivity and potency of each compound and the different animal models and treatments employed.…”

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…In the present study, we used RGFP966, an HDAC3 inhibitor (40), to examine the epigenetic effect of HDAC3 on DCM. In addition, VPA was used as the total HDACs inhibitor to detect the cardioprotection in the OVE26 type 1 diabetes mice too.…”

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala

“…Systemic infusion of the HDAC3-specific inhibitor RGFP966 enhances long-term memory (including extinction memory) in multiple memory paradigms (Bieszczad et al, 2015;Malvaez et al, 2013) but fails to enhance memory consolidation for auditory fear extinction (Bowers et al, 2015). Further, chronic systemic HDAC3 inhibition with RGFP966 is not sufficient to rescue context fear memory in a mouse model of Alzheimer's Disease (Rumbaugh et al, 2015). Studies manipulating HAT or HDAC activity directly in the amygdala, on the other hand, consistently show effects on auditory fear (Maddox et al, 2013b;Maddox et al, 2013c;Monsey et al, 2011;Yeh et al, 2004), consistent with our results.…”