Body clock gene clue in bipolar disorder

Recent research published in the journal Proceedings of the National Academy of Sciences shows that the disruption of a gene known to regulate the body clock and circadian rhythms in mice triggers behaviours similar to humans with bipolar disorder (previously called manic depression).

Bipolar disorder is characterised by alternating bouts of severe depression and mania, and affects between one and two per cent of the UK's population. Symptoms of the manic phase may include unusually high energy, less need for sleep, excessive talk, racing thoughts, euphoria, irritability, inflated self-esteem, hallucinations, addictive tendencies and delusion. The symptoms are thought to be caused by an imbalance in the levels of brain chemicals involved in mood.

Dr Colleen McClung at the University of Texas Southwestern Medical Centre in Dallas, US and colleagues genetically altered mice to have a mutation in their 'Clock' gene. The Clock gene is involved in activating many other genes in the cell, which together act to control circadian rhythms and the body clock. They affect such things as the sleep/wake cycle, activity, hormones and appetite.

'There is evidence suggesting that circadian genes may be involved in bipolar disorder', said Dr McClung, adding 'what we've done is taken earlier findings a step further by engineering a mutant mouse model displaying an overall profile that is strikingly similar to human mania, which will give us the opportunity to study why people develop mania or bipolar disorder and how they can be treated'.

In a series of laboratory tests, mice with the mutation showed hyperactivity and addictive tendencies. They slept less and showed greater sensitivity to the rewarding effects of substances such as sugary water, or cocaine. They also showed a greater willingness to engage in 'risky' activities such as exploring unsheltered areas of cages and mazes than their unaltered counterparts. 'These behaviours correlate with the sense of euphoria and mania that bipolar patients' experience', said Dr McClung.

The researchers also injected normal copies of the Clock gene back into the brains of the mice during early adulthood. Animals that received these injections reverted back to the 'normal' behaviour patterns of unaltered mice. During the study lithium, a mood-stabilising medication, was also given to the mutant mice and, when treated on a regular basis, also restored normal behaviour in the majority of the mice.

Exactly how the mutations in the Clock gene can cause these symptoms is unknown. Some research suggests that the protein made by the gene activates other genes involved in the production of dopamine, the reward-signalling molecule. Disruptions in this could disturb pleasure signalling in the brain, leading to mania and depression that characterise bipolar disorder. The researchers believe their findings could help scientists begin to understand at least the mania component of the disorder. McClung and her team are now studying other genes implicated in circadian-clock function.