Nina Wiebking, Erik Maronde and Abdelhaq Rami Pages 112 - 125 ( 14 )
Transient, severe global ischemia that arises in humans as a consequence of cardiac arrest or cardiac surgery or that is induced experimentally in animals, leads to selective and delayed neuronal death, particularly in the hippocampus. Especially, in this brain structure, clock genes are rhythmically expressed, for instance the inducible and archetypical clock gene is Period1 (Per1). An eventual involvement of its trans-activating protein products in the daytime-dependent severity of ischemia-induced cell damage is not excluded. Probably, neurons may exhibit endogenously a daytimedependent variation in the expression of predictive cell death proteins. We therefore compared the cell death machinery in the hippocampus between Per1-/-- and wildtype (WT) mice upon cerebral ischemia. Neuronal death in the hippocampal CA1-subfield, was observed in both types of mice, but the density of damaged cells in Per1-/--mice was increased by more than 23% as compared to wildtype mice. To explore the mechanisms underlying the excessive vulnerability of the hippocampus in Per1-/--mice and to address if hippocampal susceptibility inherits a daytime component, the expression of both, apoptotic and autophagic predictors of cell death was monitored. In Per1-/--mice, the expression of apoptotic/autophagic markers are altered and higher levels of the proapoptotic factors such as cytochrome c and Apaf-1 were observed as compared to WT mice. Moreover, the autophagy marker LC3B was dramatically reduced in Per1-/-- mice. Our data suggests that basal activities of apoptosis and autophagy seem to be modulated by PER1, and that the autophagic machinery is probably slowed down when this clock gene is absent. These alterations may be causal for the observed innate vulnerability of Per1-/--mice to cerebral ischemia.
Apoptosis, autophagy, cerebral ischemia, clock genes, hippocampus, selective vulnerability
Klinikum der Goethe- Universität, Dr. Senckenbergische Anatomie, Institut für Anatomie III, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany