Effects of a novel, non-toxic histone deacetylase inhibitor on memory formation in mice
Mentor 1
Karyn Frick
Mentor 2
Sarah Beamish
Start Date
1-5-2020 12:00 AM
Description
As researchers make strides to understand how the brain and memory function, memory formation continues to have many unknowns. Chromatin remodeling through epigenetic modifications, such as histone acetylation, promotes successful formation of long-term memories by increasing levels of gene expression. Research demonstrates that histone deacetylase inhibitors (HDACi) improve memory by preventing the deacetylation of core histone proteins and allowing transcriptional machinery to increase access to open chromatin. HDACi are a promising therapeutic target for memory decline, however, the memory enhancing effects of existing HDACi are precluded by their high toxicity and unwanted solubility. In collaboration with the Chemistry and Biology Departments at UWM, we have developed a novel brain-penetrant HDACi compound, Cpd1’, that shows no evidence of toxicity. Data collected from our lab indicates that Cpd1’ is capable of enhancing spatial memory in mice. However, it remains unclear the extent to which Cpd1’ modifies levels of histone acetylation in the brain. The goal of this work is to determine whether Cpd1’ modifies histone acetylation levels in a time-dependent manner in the dorsal hippocampus (DH). Mice received an intraperitoneal injection of negative control (100% DMSO), positive HDACi control sodium butyrate (0.6 g/kg NaBu), or one of three doses of Cpd1' (20,30,40 µg/g), and the DH was dissected 1 hr later. DH tissue was then homogenized so that histones were extracted, and any posttranslational modifications were kept intact. Here we present Western blot data of histone acetylation changes in the DH after 1 hr treatment. Collectively, this work represents a step forward in providing safer therapeutic treatments that can be used to treat memory decline.
Effects of a novel, non-toxic histone deacetylase inhibitor on memory formation in mice
As researchers make strides to understand how the brain and memory function, memory formation continues to have many unknowns. Chromatin remodeling through epigenetic modifications, such as histone acetylation, promotes successful formation of long-term memories by increasing levels of gene expression. Research demonstrates that histone deacetylase inhibitors (HDACi) improve memory by preventing the deacetylation of core histone proteins and allowing transcriptional machinery to increase access to open chromatin. HDACi are a promising therapeutic target for memory decline, however, the memory enhancing effects of existing HDACi are precluded by their high toxicity and unwanted solubility. In collaboration with the Chemistry and Biology Departments at UWM, we have developed a novel brain-penetrant HDACi compound, Cpd1’, that shows no evidence of toxicity. Data collected from our lab indicates that Cpd1’ is capable of enhancing spatial memory in mice. However, it remains unclear the extent to which Cpd1’ modifies levels of histone acetylation in the brain. The goal of this work is to determine whether Cpd1’ modifies histone acetylation levels in a time-dependent manner in the dorsal hippocampus (DH). Mice received an intraperitoneal injection of negative control (100% DMSO), positive HDACi control sodium butyrate (0.6 g/kg NaBu), or one of three doses of Cpd1' (20,30,40 µg/g), and the DH was dissected 1 hr later. DH tissue was then homogenized so that histones were extracted, and any posttranslational modifications were kept intact. Here we present Western blot data of histone acetylation changes in the DH after 1 hr treatment. Collectively, this work represents a step forward in providing safer therapeutic treatments that can be used to treat memory decline.
