Abstract
Alterations in histone lysine methylation and epigenetic regulators of gene expression could play a role in the neurobiology and treatment of patients diagnosed with mood spectrum disorder, including depression and anxiety. Mutations and altered expression of various lysine methyltransferases (KMTs) and demethylases (KDMs) have been linked to changes in motivational and emotional behaviors in preclinical model systems. However, it is not known whether regulators operating downstream of histone lysine methylation could affect mood-related behavior. Malignant Brain Tumor (MBT) domain ‘chromatin reader’ proteins bind to methylated histone lysine residues and associate with chromatin remodeling complexes to facilitate or repress gene expression. MBT proteins, including the founding member, L3mbtl1, maintain high levels of expression in neurons of the mature brain. Here, we exposed L3mbtl1 null mutant mice to a wide range of tests exploring cognition and mood-relevant behaviors at baseline and in the context of social isolation, as a stressor to elicit depression-related behavior in susceptible mice. L3mbtl1 loss-of-function was associated with significant decreases in depression and and anxiety in some of the behavioral paradigms. This was not associated with a more generalized neurological dysfunction because cognition and memory remained unaltered in comparison to controls. These findings warrant further investigations on the role of MBT chromatin reader proteins in the context of emotional and affective behaviors.
Highlights
Mood spectrum disorders, including depression and various anxiety disorders [1], cause significant morbidity and mortality with at least 40% of subjects only partially responding to currently available pharmacological treatments that primarily target monoamine metabolism and reuptake [2]
We reported previously that L3mbtl1-/- null mutant mice exhibit normal life expectancy, a grossly normal brain morphology and cytoarchitecture, and scorings in a locomotor coordination test that were indistinguishable from controls[29]
We asked whether depression and anxiety-related behaviors are altered in L3mbtl1-/- mice that were kept under normal ‘non-stressed’ group-housing conditions (2–3 sex-matched littermates as cage mates after weaning)
Summary
Mood spectrum disorders, including depression and various anxiety disorders [1], cause significant morbidity and mortality with at least 40% of subjects only partially responding to currently available pharmacological treatments that primarily target monoamine metabolism and reuptake [2]. Malignant Brain Tumor (MBT) domain chromatin reader proteins bind to methylated histone lysine residues and associate with chromatin remodeling complexes These include typical and atypical Polycomb repressor complexes that control expression of genes with essential roles in cell cycle regulation and early development [15,16]. Proper cell-type specific regulation of histone methylation landscapes is essential for normal brain function [18,19], and rare mono- or oligogenic forms of cognitive disease have been linked to mutations in histone lysine methyltransferase (KMT) and demethylase (KDM) genes These broadly affect the epigenetic landscapes at sites of open or repressive chromatin [5,20,21,22]. We provide a detailed account for a comprehensive behavioral assessment of adult L3mbtl null mutant mice exposed to a wide range of behavioral tests at baseline and after single housing as a social isolation stressor eliciting depression-related behavior in susceptible mice [28]
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