A new study led by researchers at the RIKEN Brain Science Institute revealed a new mouse model for major depressive episodes associated with mitochondrial dysfunction. The study is entitled “Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus” and was recently published in the journal Molecular Psychiatry.
Depression is a common debilitating condition that has been associated with defects on the mitochondria, small organelles within cells where the energy for the body is produced. The study of depression, however, has been hampered by the difficulty found in mimicking depressive episodes in animal models. Now, researchers reported that a mouse strain with a mutation in a mitochondrial DNA polymerase called Polg1, which leads to mitochondrial dysfunction, could be a potential mouse model for depression.
“Our work was motivated by the lack of animal models that accurately reproduce depressive episodes. It had been noted previously that mitochondrial diseases were linked to depression, and moreover, that patients with depressive symptoms harbored problems with mitochondrial DNA. We decided to investigate where this was happening, and started experiments with a mouse strain with a mutation in Polg1, which is involved in the replication of mitochondrial DNA,” explained the study’s senior author Dr. Tadafumi Kato in a news release.
Researchers found that mice with mutated Polg1 had a lethargic behavior associated with emotional, vegetative and psychomotor changes, and that they spontaneously underwent periodic episodes of depression-like behavior similar to depressive episodes in humans. In addition, the team identified a hotspot for deletions in mitochondrial DNA at the paraventricular thalamic nucleus (PVT), a brain region now linked for the first time to depression.
“What we were surprised to find,” noted the study’s co-lead author Dr. Takaoki Kasahara, “was that many of the female mutant mice showed symptoms similar to human depression patients. During the episodes, which began without reason and recurrently, the mice would run on their running wheels less extensively, showing they had a lack of pleasure-seeking behavior, a core feature of depression.” The animals also exhibited weight gain and increased fatigue, two other signs of depression.
Further, the animals were found to have higher levels of corticosterone (an equivalent to cortisol in humans), a molecule often reported to be elevated in patients with depression. Interestingly, when the animals were treated with an antidepressant drug, the depressive episodes were mitigated.
“We are excited about this finding,” concluded Dr. Kato, “because this could lead to new therapies for depression, which takes a major health toll on society. Furthermore, this may represent a new mechanism for the onset of depressive episodes. It is also important because if we can show that depression can be caused by mitochondrial abnormalities in an area of the brain, it would allow us to reclassify it as a brain disease with a structural cause rather than a psychiatric illness.”