Multiple oscillators assure soft margin of diurnal function and are the result of alternate splicing and later genetic rearrangement: Possible role in bipolar disorder

Abstract

Introduction Appearance of multiple effector proteins on a single receptor seems mysterious. These new effectors appear during alternate splicing, gene duplication and genomic re-arrangement during evolution. In chronobiology, this might have vital protective importance for migration to places with extreme climates. Objectives Residing on a simple light/darkness system of circadian cycle is in contrast with human cultural development. Aims Developing a model of molecular interaction to explain the BMD spectrum. Methods We classify circadian oscillators into one master (CLOCK/BMAL1) and 4 slave oscillators. The master has suppressing action on 4 parallel slave oscillators. In case of disruption of this tract, one of them reigns. Input from the retinal ganglion cells has minor effect (noise) for the parametric oscillation of the master but not slave oscillator. Mutations in the master that disrupts these feedbacks, or increases sensitivity to ganglion cells input or cause hyperactivity of the slave oscillators are explanations for BMD development. Downstream to this, a divergent set of genes ( PER1, 2, 3, NCAN, GSK3-b and CRY1 ), 2 with different functions are activated. Derangement of any of the downstream genes causes incomplete symptoms and signs. Results This model with elegant curves can successfully incorporate many laboratory and clinical findings and explains in a comprehensive way how genetic and environmental factors interact to build up disease picture and spectrum of BMD. In addition, some innovative (less intensive and with less side effects) treatment strategies can be suggested. Conclusions More research in this field is warranted.