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 now 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. Roughly 20% of patients with mitochondrial disease also have bipolar disorder, a major psychiatric disease characterized by manic and depressive episodes.
This is an abstract rendition of the paper's themes. Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signaling in the brain.
Credit: Milena Menezes Carvalho/RIKEN National Science Institute
This is immunohistochemical and electrophysiological analysis. (top) whole mouse brain, the dotted region is the dorsal raphe where COX-negative cells were more numerous in the mutants. (botton left). Close-up of the dorsal raphe. COX-negative cells are red. (bottom right) Electrophysiological analysis showed that serotonergic neurons in the mutant dorsal raphe were more excitable than in wildtype mice.
Credit: RIKEN National Science Institute
Altered serotonin functioning, on the other hand, seems to be involved in bipolar disorder because drugs that target serotonin levels can effectively treat the condition. "Our study suggests that 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," says Tadafumi Kato, research group leader at CBS. The research was published on June 8 in the journal Molecular Psychiatry.
The study started by identifying ANT1 mutations in patients with bipolar disorder. Kato and colleagues then 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 then 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--another condition that may have its roots in mitochondrial dysfunction. The ANT1 mutation does not cause bipolar disorder, says Kato, but is associated with elevated risk.
The implication of this research is that emerging therapies for the underlying mitochondrial dysfunction could one day treat bipolar disorder more successfully than today's variable serotonin-targeting drugs.
Kato TM, et al. (2018) Mitochondrial dysfunction causes hyperexcitability of serotonergic neurons. Molecular Psychiatry. doi: 10.1038/s41380-018-0074-9.
Adam Phillips | EurekAlert!
First use of vasoprotective antibody in cardiogenic shock
17.05.2019 | Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.
A nerve cell serves as a “single” for studies
15.05.2019 | Rheinische Friedrich-Wilhelms-Universität Bonn
Engineers at the University of Tokyo continually pioneer new ways to improve battery technology. Professor Atsuo Yamada and his team recently developed a...
With a quantum coprocessor in the cloud, physicists from Innsbruck, Austria, open the door to the simulation of previously unsolvable problems in chemistry, materials research or high-energy physics. The research groups led by Rainer Blatt and Peter Zoller report in the journal Nature how they simulated particle physics phenomena on 20 quantum bits and how the quantum simulator self-verified the result for the first time.
Many scientists are currently working on investigating how quantum advantage can be exploited on hardware already available today. Three years ago, physicists...
'Quantum technologies' utilise the unique phenomena of quantum superposition and entanglement to encode and process information, with potentially profound benefits to a wide range of information technologies from communications to sensing and computing.
However a major challenge in developing these technologies is that the quantum phenomena are very fragile, and only a handful of physical systems have been...
Working group led by physicist Professor Ulrich Nowak at the University of Konstanz, in collaboration with a team of physicists from Johannes Gutenberg University Mainz, demonstrates how skyrmions can be used for the computer concepts of the future
When it comes to performing a calculation destined to arrive at an exact result, humans are hopelessly inferior to the computer. In other areas, humans are...
Scientists develop a molecular recording tool that enables in vivo lineage tracing of embryonic cells
The beginning of new life starts with a fascinating process: A single cell gives rise to progenitor cells that eventually differentiate into the three germ...
29.04.2019 | Event News
17.04.2019 | Event News
15.04.2019 | Event News
17.05.2019 | Materials Sciences
17.05.2019 | Physics and Astronomy
17.05.2019 | Materials Sciences