In vivo human brain expression of histone deacetylases in bipolar disorder

Chieh-En J Tseng,Hannah E Brown,Nicole R Zürcher,Minhae Kim,Changning Wang,Amy T Peters,Mary C Catanese,Tonya M Gilbert,Joshua L Roffman,Jacob M Hooker,Anjali J Parmar,Roy H Perlis,Baileigh G Hightower

doi:10.1038/s41398-020-00911-5

Abstract

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance – positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.

Highlights

The etiology and underlying pathology of bipolar disorder (BD) are poorly understood, and their elucidation is complicated by misdiagnosis due to overlapping symptoms with other neuropsychiatric disorders including schizophrenia, unipolar depression, and impulse control[1]
A recent systematic analysis of genome-wide association study (GWAS) data incorporating gene pathway analysis, found that HDAC2 may be linked to increased genetic risk for BD through its involvement in the development of the amygdala, nucleus accumbens and hippocampus[8]
BD is characterized by recurrent episodes of altered mood involving disruptions in emotion regulation and cognitive processes which lead to overall functional impairment

Summary

Introduction

The etiology and underlying pathology of bipolar disorder (BD) are poorly understood, and their elucidation is complicated by misdiagnosis due to overlapping symptoms with other neuropsychiatric disorders including schizophrenia, unipolar depression, and impulse control[1]. Polygenic risk has explained some of the heritability of BD, which is estimated at ~60–80%2–4, and environmental factors including childhood trauma and life events. Genetic association and clinical pharmacology have been used to identify a potential role for HDACs in BD. A recent systematic analysis of genome-wide association study (GWAS) data incorporating gene pathway analysis, found that HDAC2 may be linked to increased genetic risk for BD through its involvement in the development of the amygdala, nucleus accumbens and hippocampus[8]. Hyper-activity was reduced by HDAC inhibition in preclinical models of mania[12,13]. These observations beg the question of whether HDACs may represent a direct mechanistic link to BD

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