Application of Pleiades MiniPromoters for studying the role of NR2E1 in neural stem cells and mania-like behaviour

Severe psychiatric disorders affect three to five per cent of Canadians. One of these diseases is called Bipolar Affective Disorder Type I (BPDI). People with this disorder manifest many unusual manic behaviours. They typically do not sleep much, feel like they are on top of the world, have racing thoughts and are easily distracted. However, most BPDI patients also have depressive episodes and 15 per cent will commit suicide. The recurrence rate for BPDI is 90 per cent, making it a life-long disorder. Unfortunately, it is incurable and difficult to manage with current therapeutics. The brain transcription factor Nr2e1 controls the proliferation and differentiation of neural stem cells, which are required for the formation of neurons (neurogenesis). Some people with BPDI show dysplasia of forebrain and neurogenic regions and treatment that improve symptoms of bipolar disorder are known to stimulate neurogenesis. Mice that have a non-functional version of the Nr2e1 gene (dubbed ’fierce’ mice) display similar severe mania-like behaviour and defects in neurogenesis as observed in people with BPDI. Charles de Leeuw is investigating the use of MiniPromoters – DNA constructed from small conserved regions of a gene that tell it when and where it should turn on – to affect gene expression in specific brain regions of fierce mice. He will use the MiniPromoters to deliver Nr2e1 to the neural stem cells that are defective but also in the neurons that are generated from defective stem cells, both types of cells which are involved in the fierce mice defects. If he is able to prompt the gene to be turned on in the correct area of the brain, de Leeuw anticipates he will be able to ‘cure’ some of the mania-like behaviours in mice. His goal is to determine the potential for treating the genetic cause of BPDI through the use of MiniPromoters and human NR2E1. His experiments will also help shed light on the neurodevelopmental causes of manic behaviour.