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.