A Marked Effect of Electroconvulsive Stimulation on Behavioral Aberration of Mice with Neuron-Specific Mitochondrial DNA Defects

We developed transgenic (Tg) mice modeling an autosomally inherited mitochondrial disease, chronic progressive external ophthalmoplegia, patients with which sometimes have comorbid mood disorders. The mutant animals exhibited bipolar disorder-like phenotypes, such as a distorted day–night rhythm and a robust activity change with a period of 4–5 days, and the behavioral abnormalities were improved by lithium. In this study, we tested the effect of electroconvulsive stimulation (ECS) on the behavioral abnormalities of the model. Electroconvulsive therapy, which has long been used in clinical practice, provides fast-acting relief to depressive patients and drug-resistant patients. We performed long-term recordings of wheel-running activity of Tg and non-Tg mice. While recording, we administrated a train of ECS to mice, six times over two weeks or three times over a week. The treatment ameliorated the distorted day–night rhythm within three times of ECS, but it had no effect on the activity change with a period of 4–5 days in the female mice. To study the mechanism of the action, we investigated whether ECS could alter the circadian phase but found no influence on the circadian clock system. The potent and fast-acting efficacy of ECS in the mutant mice supports the predictive validity of the mice as a model of bipolar disorder. This model will be useful in developing a safe and effective alternative to lithium or electroconvulsive therapy

Effect of ECS. Mice were oxygenized and delivered ECS three times within a week (days 54, 56, and 58; shown in Fig. 1B).

<p>Wheel-running activity (A), delayed (B) and anticipatory (C) activity indices, and day-to-day variation in activity (D) were estimated on the basis of the activity levels before (Pre) and after (Post) the treatment (days 11–53 and 66–89, respectively). Values from individual male mice are indicated by closed circles connected with solid lines, and values from individual female mice are indicated by closed triangles connected with dashed lines. Delayed activity index of Tg mice and anticipatory activity index of both Tg and non-Tg mice were significantly lowered by ECS. (E) Time courses of delayed and anticipatory activity indices of male Tg mice receiving ECS. Each color of line represents different individuals (<i>n</i> = 9). The week when three ECS treatments were delivered is indicated by a red background.</p

No influence of ECS on the circadian clock.

<p>Double-plotted activity records of representative mice receiving one ECS (red triangles) at different times of the day: circadian time (CT) 0, 4, 8, 12, 16, and 20. CT0–12 is the subjective light phase, and CT12–24 is the subjective dark phase. The light and dark periods are indicated by white and gray backgrounds, respectively. Onset of activity shown by green lines was used as the reference phase for the determination of phase shift.</p

Wheel-running activity records of representative mice receiving ECS.

<p>Mice were delivered ECS (red triangles) six times (A) or three times (B). The light and dark periods (12:12 h) are indicated by white and gray backgrounds, respectively.</p

Single-cell temperature mapping with fluorescent thermometer nanosheets

Recent studies using intracellular thermometers have shown that the temperature inside cultured single cells varies heterogeneously on the order of 1°C. However, the reliability of intracellular thermometry has been challenged both experimentally and theoretically because it is, in principle, exceedingly difficult to exclude the effects of nonthermal factors on the thermometers. To accurately measure cellular temperatures from outside of cells, we developed novel thermometry with fluorescent thermometer nanosheets, allowing for noninvasive global temperature mapping of cultured single cells. Various types of cells, i.e., HeLa/HEK293 cells, brown adipocytes, cardiomyocytes, and neurons, were cultured on nanosheets containing the temperature-sensitive fluorescent dye europium (III) thenoyltrifluoroacetonate trihydrate. First, we found that the difference in temperature on the nanosheet between nonexcitable HeLa/HEK293 cells and the culture medium was less than 0.2°C. The expression of mutated type 1 ryanodine receptors (R164C or Y523S) in HEK293 cells that cause Ca2+ leak from the endoplasmic reticulum did not change the cellular temperature greater than 0.1°C. Yet intracellular thermometry detected an increase in temperature of greater than ∼2°C at the endoplasmic reticulum in HeLa cells upon ionomycin-induced intracellular Ca2+ burst; global cellular temperature remained nearly constant within ±0.2°C. When rat neonatal cardiomyocytes or brown adipocytes were stimulated by a mitochondrial uncoupling reagent, the temperature was nearly unchanged within ±0.1°C. In cardiomyocytes, the temperature was stable within ±0.01°C during contractions when electrically stimulated at 2 Hz. Similarly, when rat hippocampal neurons were electrically stimulated at 0.25 Hz, the temperature was stable within ±0.03°C. The present findings with nonexcitable and excitable cells demonstrate that heat produced upon activation in single cells does not uniformly increase cellular temperature on a global basis, but merely forms a local temperature gradient on the order of ∼1°C just proximal to a heat source, such as the endoplasmic/sarcoplasmic reticulum ATPase

Systematic analysis of exonic germline and postzygotic de novo mutations in bipolar disorder

The significance of rare and de novo variants in bipolar disorder is not well understood. Here, the authors have analyzed whole exome/genome data from trios to identify deleterious de novo variants associated with bipolar disorder