Behavioral Alterations in Mice Carrying Homozygous HDAC4 A778T Missense Mutation Associated With Eating Disorder.

Kevin C Davis,Michael Lutter,Samuel R Rodeghiero,Kenji Saito,Huxing Cui,Brandon A Toth

doi:10.3389/fnins.2020.00139

Kevin C Davis, Michael Lutter + Show 4 more

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https://doi.org/10.3389/fnins.2020.00139

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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.

Highlights

Eating disorders (EDs), such as anorexia nervosa (AN) and bulimia nervosa (BN), are serious mental illnesses thought to develop as a result of complex gene-environment interaction (Hinney et al, 2010; Carmichael and Lockhart, 2012; Lutter et al, 2016; Baker et al, 2017)
By combining genetic linkage analysis and whole exome sequencing in two independent families in which multiple members are affected by EDs, we have previously identified two missense mutations in the estrogen-related receptor alpha (ESRRAR188Q) and histone deacetylase 4 (HDAC4A786T) genes, respectively (Cui et al, 2013), that increase the risk of developing an ED
In the followup mouse studies, we found that Esrra knockout mice display behavioral deficits relevant to EDs, including reduced food intake, decreased motivation to work for high-fat diet (HFD), and social subordination (Cui et al, 2015)

Summary

Introduction

Eating disorders (EDs), such as anorexia nervosa (AN) and bulimia nervosa (BN), are serious mental illnesses thought to develop as a result of complex gene-environment interaction (Hinney et al, 2010; Carmichael and Lockhart, 2012; Lutter et al, 2016; Baker et al, 2017). By combining genetic linkage analysis and whole exome sequencing in two independent families in which multiple members are affected by EDs, we have previously identified two missense mutations in the estrogen-related receptor alpha (ESRRAR188Q) and histone deacetylase 4 (HDAC4A786T) genes, respectively (Cui et al, 2013), that increase the risk of developing an ED. Mice heterozygous for Hdac4A778T [corresponding to the human HDAC4A786T mutation which we previously reported to be a gain-of-function mutation in the catalytic domain of HDAC4 to increase gene suppression in cultured cells (Cui et al, 2013)] on a mixed C57BL/6 and 129/Sv genetic background display altered feeding behaviors depending on housing condition (Lutter et al, 2017). Our results may indicate a complex role for Hdac4A778T mutation in affecting mouse behaviors in different genetic background and growth environment with sex-dependent manner

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