Laboratory of Cellular and Molecular Pathophysiology: Research Annual Report 2003

Section Head: Dr. Jerry Warsh

Research in the Laboratory of Cellular and Molecular Pathophysiology Section investigates the cellular and molecular processes that lead to the development of the major psychoses, principally bipolar affective disorder. We also explore the molecular pharmacology of current mood stabilizer and antidepressant medications to understand their mode of action, in hopes of finding more specific cellular targets for drug action against which new drugs can be developed. The research team includes Dr. Jerry Warsh, clinician scientist, Dr. Peter Li, senior basic scientist, and their graduate student and postdoctoral trainees.

Our team is internationally recognized for groundbreaking, innovative research on intracellular signalling abnormalities; these abnormalities are now recognized to play a critical role in the predisposition for, and development of, bipolar I disorder.

The closer we come to understanding the specific chain of cellular disturbances that lead to bipolar disorder, the more effectively we can work to develop new strategies to treat and prevent it. To reach our goals, we have set up new equipment and are developing techniques to measure cellular changes in patients. This measurement infrastructure will help us translate our research findings into clinical tests, which may make it easier to diagnose subtypes of bipolar disorder and guide the choice of mood-stabilizer medications in treatment. Our research also sets the stage for the development of new drugs to treat this disorder and prevent relapses.

The important directions of the research in the section have been recognized in recent research grants from the Canadian Institutes for Health Research, the Ontario Mental Health Foundation and the National Alliance for Research in Schizophrenia and Depression.

cAMP Signalling System and Bipolar Disorder

During the past year, we elaborated more in-depth details of the nature and extent of abnormalities in the cyclic adenosine monophosphate (cAMP) signalling system in brain of people with bipolar disorder. These abnormalities appear to funnel through a key receiving protein, cAMP-dependent protein kinase. This protein "translates" dissonant signals into cellular signalling cascades. The resilience of cells in brain tissue can be affected if the cAMP signalling system is disrupted.

We have found key evidence that cAMP signalling is increased in bipolar disorder in specific brain regions involved in mood regulation. Also, the target protein (cAMP-dependent protein kinase) changes its composition, levels and response in a way that may be maladaptive.

The patterns of changes in cAMP-dependent protein kinase suggest that the processes that regulate its composition and positioning have been changed in a way that affects its breakdown in brain neurons. This is a second, key piece of evidence we have found, suggesting that altered proteomic mechanisms are likely involved in the development of bipolar I disorder.

Calcium Signalling in Bipolar Disorder

We continue our in-depth analysis of parts of the intracellular calcium signalling system, which is also disturbed in bipolar disorder. Calcium signalling also plays critical roles in maintaining the resilience of cells: disruption of calcium signalling can lead to cell death. The abnormalities found in the cAMP signalling cascade in bipolar disorder take on even greater importance in light of their relationship with calcium signalling: there are several bridging points at which cAMP signalling modifies what the calcium signalling systems are doing.

Molecular Pharmacology of Mood Stabilizers 

Investigations on the molecular pharmacology of mood stabilizers have led us to identify several novel genes that are regulated by long-term lithium treatment. One of the genes codes for a key enzyme in the metabolism of a type of sugar, inositol; inositol is converted to chemical messengers, the high-energy inositol polyphosphates. The other gene encodes a membrane-spanning protein that may act as a "signal complex," co-ordinating the localized formation of signalling lipids and the positioning of the target signalling protein, protein kinase C, at the inner side of nerve cell membrane.

These observations have uncovered previously unknown targets of lithium. Because these targets are affected in the same range as the blood levels achieved during lithium treatment, they are likely related to lithium's therapeutic actions.

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