Schizophrenia Research Forum - A Catalyst for Creative Thinking

Disorganized Mouse May Point to Psychopathology

November 1, 2013. Among the symptoms of schizophrenia and bipolar disorder is disordered thinking. A new study in mice shows how a minor change in just one protein can muck up the memory needed for repeating a simple task such as running a maze. The fact that this protein change might increase the risk for psychiatric disorders makes it of particular interest.

The study, published October 16 in the journal Neuron, is based on research from the laboratory of Nobel laureate Susumu Tonegawa at the Massachusetts Institute of Technology, Cambridge, which suggested that changes in the protein calcineurin very slightly increase the risk for developing schizophrenia.

As co-lead authors Junghyup Suh and David J. Foster, the latter at Johns Hopkins University, report in the new study, the brain cells of mice with the altered calcineurin protein don't replay the memory of running a maze in the same way normal mice do. While this is not proof that disordered thinking in mental illness is related to calcineurin changes, it does provide clues about how the brain can be altered very subtly and possibly create problems in complex behavior such as learning and using spatial cues.

In an editorial accompanying the article, Patricio O'Donnell of Pfizer, Inc., writes that an additional contribution of the paper is to show that animal models of human disorders, while not modeling the disease itself, can still provide clues to individual underlying biological changes that add up to disorders such as schizophrenia or bipolar disorder.

What Makes a Manic Mouse?
Researchers led by Huda Zoghbi of Baylor College of Medicine in Houston, Texas, report that they have engineered a mouse that could be called manic, or at the very least, hyperactive. The mouse produces 50 percent more of a protein called Shank3, which holds special interest for scientists because disruptions in the gene that produces Shank3 are found in some people with autism spectrum disorders, intellectual disability, and schizophrenia, as well as epilepsy and other disorders.

Their mouse "model" of mania, which could provide insight into human bipolar disorder, is not the only evidence Zoghbi and her colleagues reported in their paper published October 23 in the journal Nature. They also located two patients who have Shank3 gene mutations that cause them to produce too much of the protein, very much like the mutant mice. One had been diagnosed with bipolar disorder and the other with attention deficit hyperactivity disorder (ADHD), and both had seizure disorders.

Whether or not the mouse with too much Shank3 really has a mania that models human bipolar disorder, the researchers will be able to study how Shank3 mutations cause psychiatric symptoms. In this paper, they report that Shank3 normally acts as a scaffold for other proteins to hang on to. When there is too much Shank3, brain cells become overactive, firing off more electrical signals than usual. (For more details, see the related news story.)—Hakon Heimer.