Neuroimaging and post mortem brain studies implicated involvement of several brain regions in pathophysiology of bipolar disorder (BD). However the responsible neural system, such as substantia nigra dopaminergic neurons in Parkinson’s disease, has not been identified.
Based on the mitochondrial hypothesis of BD, we previously created the transgenic mice (Tg mice) expressing defective mitochondrial DNA (mtDNA) polymerase in forebrain neurons and they exhibited BD-like phenotypes. In Tg mice, these phenotypes were caused by functional alternations due to accumulation of aberrant mtDNA. Therefore, we hypothesized that the most damaged region in Tg mice brain could be revealed by the quantitative analysis of aberrant mtDNA. The results would also provide some insights into identification of the neural system responsible for BD.
In this study, we conducted semi-comprehensive quantitative mapping of deleted mtDNA (Δ-mtDNA) using laser microdissection and quantitative PCR technique. As a result, regional selectivity of Δ-mtDNA accumulation was observed and large amounts of Δ-mtDNA were detected in mood disorder-related regions including mouse equivalent of subgenual cortex and nucleus accumbens. The most prominent accumulation of Δ-mtDNA was detected in paraventricular thalamic nucleus (PVT), which plays a role in stress response and circadian behavior and has connections with many mood disorder-related regions such as subgenual cortex, insular cortex, nucleus accumbens, amygdala, suprachiasmatic nucleus and midbrain monoaminergic neurons.
These results implicate the putative mechanism of how mitochondrial dysfunction results in BD. Further analysis of PVT, a new candidate region of BD, is warranted.