Frontiers in Neuroscience (Feb 2020)
Behavioral Alterations in Mice Carrying Homozygous HDAC4A778T Missense Mutation Associated With Eating Disorder
Abstract
Eating disorders (EDs) are serious mental illnesses thought to arise from the complex gene-environment interactions. DNA methylation patterns in histone deacetylase 4 (HDAC4) locus have been associated with EDs and we have previously identified a missense mutation in the HDAC4 gene (HDAC4A786T) that increases the risk of developing an ED. In order to evaluate the biological consequences of this variant and establish a useful mouse model of EDs, here we performed behavioral characterization of mice homozygous for Hdac4A778T (corresponding to human HDAC4A786T) that were further backcrossed onto C57BL/6 background. When fed high-fat diet, male, but not female, homozygous mice showed a trend toward decreased weight gain compared to their wild-type littermates. Behaviorally, male, but not female, homozygous mice spent less time in eating and exhibited reduced motivation to work for palatable food and light phase-specific decrease in locomotor activity. Additionally, homozygous Hdac4A778T female, but not male, mice display social subordination when subjected to a tube dominance test. Collectively, these results reveal a complex sex- and circadian-dependent role of ED-associated Hdac4A778T mutation in affecting mouse behaviors. Homozygous Hdac4A778T mice could therefore be a useful animal model to gain insight into the neurobiological basis of EDs.
Keywords