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Lunenfeld researcher first in Canada to discover new clue in the development of mania and bipolar disorder

(October 24, 2011 – Toronto, ON) Bipolar disorder and mania are debilitating psychiatric disorders characterized by extreme mood swings. In the manic phase, people are likely to experience phases of euphoria, grandiosity, and greater risk taking.

According to a recent government report, over half a million Canadians aged 15 or older reported that sometime in their life they had experienced symptoms of a manic episode.

Now, Greer S. Kirshenbaum, a doctoral student, and her colleagues in Dr. John Roder’s lab at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital are one step closer to uncovering the genetic basis of the disease. Their findings were published in the October 24 issue of Proceedings of the National Academy of Sciences.

The team studied genetically engineered mice that lack the sodium-potassium ATP-ase gene (known as ‘NKA’) and found that reduced NKA activity alters calcium levels. This triggers a cascade of signals in a communication pathway (termed ERK) previously known to be linked to bipolar disorder. As a result, the normal pattern of neuronal activity is disrupted, altering mood and behaviour.

“These findings are very exciting to see given that they offer the prospect of new therapies for bipolar disorder,” said Greer.

“Our goal is to develop more effective treatments that target the root causes of the disorder.” Several recent studies have shown that current pharmacological treatments for bipolar disorder often fail to adequately address the most debilitating symptoms and can cause harsh side effects. Although the role of calcium channels and the ERK pathway have previously been investigated in psychiatric illnesses, the ATP-ase gene represents a new therapeutic target.

The study showed that the NKA inactivated mice displayed increased exploratory behaviour, faster walking, reduced sleeping times, greater risk-taking behavior, and greater impulsivity—all of which are remarkably similar to the patterns of behaviour seen in humans during manic episodes of bipolar disorder.

In addition to these symptoms, Greer and her team found that the mania-like behavior in the mice was reduced by treatment with lithium and valproic acid, which are two of the most commonly prescribed mood stabilizers. They also treated manic behavior with two novel compounds that reduce ATP-ase activity.

“This new research follows up on a 50 year-old hypothesis that the sodium-potassium ATP-ase gene is involved in bipolar disorder, but this is the first genetic model that has been developed to study its role in mania and bipolar disorder,” said Greer. “What is most notable is that the mouse model can be readily applied to studying the gene’s effects in humans as well.” The study received support from the Canadian Institutes of Health Research as well as the Ontario Mental Health Foundation.

"This paper is an important step forward in understanding bipolar disorder, which like many psychiatric disorders, has few good animal models,” said Dr. Albert Wong, an Associate Professor at the University of Toronto and a scientist at the Centre for Addiction and Mental Health. “The most effective treatment for bipolar disorder remains lithium, which is also one of the oldest drugs in psychiatry. Animal models such as the NKA-deficient mouse provide an entry-point into the neurobiology of mania, and a platform on which to test new potential treatments."

In her earlier work on the genetics of depression, Greer showed that chronic stress caused a decrease in neuronal NKA activity in mice that had only one functional copy of the ATP-ase gene. Together the work shows that mood may be regulated by the activity of NKA.

Greer will begin post-doctoral studies at Columbia University next month, where she will pursue research in neurogenesis.



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