Manic-depressive mice

Scientists have bred mice with a model of bipolar disorder

Elizaveta Ivtushok, N+1

Scientists have managed to breed mice with a model of bipolar affective disorder for the first time. To do this, they created genetically modified animals, in the pyramidal neurons of whose brain ankyrin-G – protein was removed, the absence or mutation of which is associated with the risk of bipolar disorder in humans. Scientists have found in the bred mice all the symptoms of a mental disorder: bouts of manic behavior and depression caused by stress. The article was published in the journal Proceedings of the National Academy of Sciences.

Bipolar affective disorder (formerly known as manic-depressive psychosis) – this is a mental illness characterized by frequent alternation of periods of increased activity (mania) and depressive episodes. The neural mechanisms of the onset and progression of the disease are still not fully understood; recent studies, however, show that the ANK3 gene is responsible for the risk of bipolar disorder. Due to the same lack of knowledge of the disease, the methods of its treatment are also limited: at the moment, the most effective of them is taking lithium drugs, which are prescribed during the manic phase of the disease. To find other, more effective ways of treatment, it is important for scientists to learn how to study bipolar disorder in the laboratory (and on the example of model organisms).

The authors of the new work have created a model of bipolar disorder in a living organism. To do this, they created genetically modified mice that have pyramidal neurons (the main excitatory neurons of the brain) ankyrin-G protein, which is encoded by the ANK3 gene, was removed from the forebrain. The expression of this protein was checked post mortem after the end of the experiment: the analysis revealed its reduced amount. The behavior of mice was studied at the age of seven months. Mice from the active and control groups were kept in the same conditions, there were no obvious differences in weight and appearance among individuals from both groups.

Ankyrin-G expression (light green) in the neurons of the mouse brain from the control group (left) and in the neurons of the genetically modified mouse. Drawings from an article in PNAS.

To study their activity, the mice were placed in a special cage, which housed infrared sensors that respond to movement. Thus, the "triggering" of sensors served as an indicator of mouse activity (every five minutes during a 50-minute observation and then every hour during a day-long observation). Scientists have found that mice from the active experimental group are characterized by symptoms of increased activity (the same as in manic syndrome): in general, they were twice as active as the mice from the control group, and their activity increased at night.

The number of triggers of the infrared sensor during the 50-minute study (A) and 24-hour study (B). On the y axis: the number of triggers every five minutes (A) and every hour (B). The red color indicates mice from the active experimental group, blue – from the control group.

To make sure that the increased activity of mice is due to manic behavior, and is not, for example, attention deficit hyperactivity disorder (ADHD), the mice were injected with methylphenidate, a psychostimulant that reduces the activity of patients with ADHD, but can cause hyperactivity in people without this syndrome. The administration of the drug increased the activity of mice in both the control and active groups, indicating that the increased activity was not due to the presence of ADHD.

The number of infrared sensor triggers during a 50-minute study. The mice of the active group are indicated in red, the mice from the control group are indicated in blue before (shaded squares) and after (empty squares) taking methylphenidate.

Then the scientists tested the effect of two drugs prescribed for this phase of bipolar disorder on mice with manic syndrome: lithium and valproic acid. Both drugs were effective and reduced the activity of manic mice to the level of the control group.

The number of infrared sensor triggers during a 50-minute study of mice before and after taking lithium (G) and valproic acid (H). The mice of the active group are indicated in red, the mice from the control group are indicated in blue before (colored squares) and after (empty squares) taking the drug.

After studying the manic behavior of individuals, scientists caused stress in mice due to social defeat: animals were put in a cage for a few minutes every day for two weeks to a larger individual. This was done in order to cause depressive symptoms in mice, which in bipolar disorder occur most often under the influence of stress (as opposed to the manic phase, which appears spontaneously).

Changes in the behavior of experimental mice after their social defeat were studied using two experimental sites: an elevated plus maze and a deep container with water. The plus-shaped maze consists of two types of sleeves (open and closed) and is used to study anxiety in laboratory animals: restless individuals spend less time in open areas of the maze due to fear of falling, while normal individuals explore the entire territory. A container of water is used to study the behavior of an animal in a life-threatening situation.

Analysis of the behavior of mice before and after social defeat showed that mice from both the control and active groups became less active, and the activity of mice with bipolar disorder decreased by half, while the activity level of mice from the control group decreased, but not significantly. Mice from the active group also spent ten times less time in the open arms of the plus–shaped maze and five times more time in a stationary state in a container with water after social defeat. This behavior of mice, according to scientists, indicates that the stress caused by them caused the appearance of depressive symptoms – one of the characteristic phases of bipolar disorder.

Activity on the site with infrared sensors (A), in the open arms of the plus maze (B) and time spent in a calm state in a deep container with water (C). The mice from the active group are indicated in red, the control group is indicated in blue (colored markers are before social defeat).

The new work is the first study in which scientists were able to breed mice with a model of bipolar disorder and all the mental disorders characteristic of this disease. Previously, scientists have already tried to breed mice with this disease by suppressing the activity of the ANK3 gene, but in the last experiment, scientists traced only part of the symptoms characteristic of the disorder.

Mice are often used as model organisms to study various mental illnesses, for example, schizophrenia.

Portal "Eternal youth" http://vechnayamolodost.ru  20.09.2017