Clock genes, feedback loops and their possible role in the etiology of bipolar disorders: an integrative model.

Clock genes, which are found in all higher organisms including humans, play a central role in the generation and control of circadian rhythms. For example, the amount of protein encoded by the per gene in mice oscillates with a circadian frequency. The per gene is activated by a constitutively expressed heterodimeric protein encoded by the bmal1 and clock genes, and this activation is suppressed by the PER protein itself. The negative feedback of the PER protein on the expression of the per gene provides a framework for a basic circadian autoregulatory loop in mammals. These elements of biomolecular feedback loops are interpreted within a system theory as an elementary behavioral cycle consisting of intentional programs (the per gene), environmental objects (the BMAL1-CLOCK heterodimer) and the experiential realization of the intended programs (the level of PER protein). This single model enables the deduction of disturbances, which can be transferred to the criteria of bipolar disorders. It is hypothesized that mutations in clock genes lead to disturbances in molecular feedback loops, which on a behavioral level could appear as bipolar disorders. Finally, some implications for research and treatment of bipolar disorders are discussed. Copyright 2000 Harcourt Publishers Ltd.