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Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signaling in the brain. These two pathways have been separately implicated in bipolar disorder, but the link between levels of the neurotransmitter serotonin and mitochondrial dysfunction had not been established.
Researchers at the RIKEN Center for Brain Science (CBS) in Japan report that mitochondrial dysfunction affects the activity of serotonergic neurons in mice with mutations of ANT1. Mitochondria are the vital organelles that deliver energy to all cells and mitochondrial damage has been found, for example, in brain imaging of bipolar patients and in post-mortem brains.
Altered serotonin functioning, seems to be involved in bipolar disorder because drugs that target serotonin levels can effectively treat the condition. Mitochondrial dysfunction can alter activity of serotonergic neurons in bipolar disorder, and this is the first time these two lines of evidence have been linked. The study started by identifying ANT1 mutations in patients with bipolar disorder. Researches looked at mice lacking the ANT1 gene in the brain only. Compared with non-mutant mice, the mitochondria in these knockout mice could not retain calcium and had leakier pores.
The ANT1 -mutant mice also showed lower impulsivity in behavior tests, and consistent with this, their brains showed elevated serotonin turnover. This hyper-serotonergic state is likely a result of a cascade of changes that starts with the loss of the ANT1 gene and the resulting dysfunctional mitochondria. Enhanced serotonergic activity may further impair mitochondria in a vicious cycle.
Serotonergic neurons were found to deteriorate in a brain area called the dorsal raphe, which is a region also affected in Parkinson’s disease. The ANT1 mutation does not cause bipolar disorder but is associated with elevated risk. The implication of this research is that emerging therapies for the underlying mitochondrial dysfunction could treat bipolar disorder more successfully than the present variable serotonin-targeting drugs.
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