A genetic mouse model could help improve therapies for bipolar disorder

March 28, 2014
Figure 1: A genetic mouse model shows that suppression of myo-inositol has the same effect on behavior as lithium treatment for bipolar disorder. Credit: Thinkstock

Bipolar disorder is a mental illness characterized by episodic mood swings that can impair the ability of sufferers to function in ordinary life. Lithium is one of the most effective treatments for the disorder, but the biological basis for its effectiveness has remained unclear. Tetsuo Ohnishi and colleagues from the RIKEN Brain Science Institute and RIKEN BioResource Center have now produced a genetic mouse model to show that lithium's therapeutic effect stems from its suppression of a biomolecule called myo-inositol.

Lithium has various biological effects, one of which is to inhibit the enzyme myo-inositol monophosphatase (IMPase). This enzyme normally synthesizes myo-inositol, which is an important signaling molecule in cells. It has been unclear, however, whether 's effect on myo-inositol levels is what makes it effective in treating bipolar disorder.

"We set out to examine whether or not the inositol depletion hypothesis of lithium action is real by creating a in which cellular myo-inositol is reduced genetically," explains Ohnishi. "If the hypothesis is correct, the mouse model should mimic lithium's biological effects." The mouse model created by the research team was genetically engineered to express mutant forms of IMPase, which prevented the animals from producing myo-inositol.

"Lithium exerts antimanic and antidepressive effects in humans, and prolongs the circadian period," says Ohnishi. "We found an antidepressive trait in our mouse model in various tests, and the circadian period of the model mice was longer than in wild-type controls. Collectively, the data suggest that cellular inositol depletion exerts lithium's effects."

The mutation also had another unexpected effect, causing defects in the development of the lower jaw and ribs in some mice. Adding myo-inositol to the drinking water of the pregnant mothers prevented these developmental problems, showing that the lack of myo-inositol was responsible. This effect has never been seen before, and Ohnishi thinks it could provide more clues about the effects of lithium. "The molecular mechanisms evoking developmental defects and behavioral effects probably overlap at the molecular level," he notes.

The researchers believe that investigating these overlapping points could potentially reveal the molecular mechanism of lithium in the brain, as well as the mechanism responsible for developmental abnormalities. Ohnishi is also confident that the findings will assist in improving the treatment of . "Some patients do not respond to lithium, and beneficial concentrations are close to the toxic range. Our findings may motivate therapeutic companies to develop new drugs that target IMPase."

Explore further: The hunt for a successor to lithium for bipolar disorder

More information: Ohnishi, T., Murata, T., Watanabe, A., Hida, A., Ohba, H., Iwayama, Y., Mishima, K., Gondo, Y. & Yoshikawa, T. "Defective craniofacial development and brain function in a mouse model for depletion of intracellular inositol synthesis." The Journal of Biological Chemistry advance online publication, 19 February 2014 (DOI: 10.1074/jbc.M113.536706). http://dx.doi.org/10.1074/jbc.M113.536706

Related Stories

The hunt for a successor to lithium for bipolar disorder

March 27, 2013
Toxicity problems and adverse side effects when taking lithium, the mainstay medication for treating bipolar disorder, are fostering a scientific hunt for insights into exactly how lithium works in the body—with an eye ...

Two SNPs predict lithium response in bipolar I disorder

December 31, 2013
(HealthDay)—For patients with bipolar I disorder, two single nucleotide polymorphisms (SNPs) in glutamate decarboxylase-like protein 1 (GADL1) predict response to lithium, according to a study published online Dec. 25 in ...

Body clocks may hold key for treatment of bipolar disorder

March 13, 2012
Scientists have gained insight into why lithium salts are effective at treating bipolar disorder in what could lead to more targeted therapies with fewer side-effects.

Lithium reduces risk of suicide in people with mood disorders

June 28, 2013
The authors say the drug "seems to reduce the risk of death and suicide by more than 60% compared with placebo" and suggest this review "reinforces lithium as an effective agent to reduce the risk of suicide in people with ...

Recommended for you

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

New vaccine production could improve flu shot accuracy

July 24, 2017
A new way of producing the seasonal flu vaccine could speed up the process and provide better protection against infection.

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.