Bipolar Disorder Linked With Gene Expression in Unexpected Brain Region

Brain DNA
Brain DNA
New findings underline the potential importance of signaling pathways in the striatum for understanding bipolar disorder pathophysiology.

New findings by scientists at The Scripps Research Institute in Jupiter, Florida, reveal striatum-specific genetic associations with bipolar disorder.

An estimated 2.4% of people worldwide are estimated to have bipolar spectrum disorders, which are a significant cause of neuropsychiatric disability. The impulsive and risk-taking behavior observed during manic episodes may stem from impaired reward processing and implicate the striatum as a possible region of dysfunction in bipolar disorder (BD). Neuroimaging data reveal variations between BD subjects and controls in striatal volume, functional activity, and dopamine transporter availability.

BD heritability estimates are high–between 59–85%, and if the striatum has a role in BD pathophysiology, relevant gene expression changes might be expected in this region. Before the current study, however, transcriptomic research using postmortem brain samples of people with BD has focused primarily on cortical regions.

The study published in Molecular Psychiatry is the first to report the transcriptome sequencing of postmortem striatum samples from individuals diagnosed with BD (n=18) and control individuals (n=17), and they also performed analyses with bioinformatics tools. Changes in expression were observed in 14 genes, and 8 of these were validated by qPCR. These included several immune system genes–LILRA4 and FCGBP, as well as NLRC5 and S100A12, which have been associated with BD and schizophrenia–and various non-protein coding genes.

Functional pathway analysis detected an “enrichment of upregulated genes across many immune/inflammation pathways and an enrichment of downregulated genes among oxidative phosphorylation pathways,” the authors reported. Twenty modules of highly interconnected genes were identified in co-expression network analysis, and 2 of the modules were enriched in BD susceptibility single-nucleotide polymorphisms (SNPs). Notably, the module found to have the “highest genetic association signal for BD, which contained many genes from signaling pathways, was also enriched in markers characteristic of gene expression in dorsal striatum medium spiny neurons…,” they wrote.

The current results linking the striatum with BD etiology at the gene level are in line with research showing the same association at the anatomical level. In 2 functional imaging studies, for example, decreased activity was found in the dorsal striatum of individuals with BD during reward-related tasks.

The authors speculate that in some BD patients, genetic susceptibility affecting striatal MSN signaling, combined with chronic inflammatory stress, may impair striatal circuits and lead to some of the BD-associated behaviors.

These findings underline the potential importance of striatal signaling pathways in understanding BD pathophysiology. Future human and animal research on the topic “may shed additional light on the role of specific molecular pathways and neuronal circuits in the etiology of BD, and provide new targets for the development of therapies,” the authors concluded.

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Pacifico R, Davis RL. Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder. Molecular Psychiatry. 2016; doi:10.1038/mp.2016.94