Inducible cAMP early repressor (ICER)-evoked delayed neuronal death in the organotypic hippocampal culture

Programmed cell death involving gene regulation and de novo protein synthesis is a major component of both normal development and a number of disease conditions. Hence, knowledge of its mechanisms, especially transcription factors, that regulate expression of the genes involved in neurodegenerative disorders is of great importance. cAMP-responsive element-binding protein (CREB) has repeatedly been implicated in the neuronal survival. In the present study we showed that inducible cAMP early repressor (ICER), an endogenous CREB antagonist, is expressed during both excitotoxic and spontaneous neuronal cell death in organotypic hippocampal slice cultures in vitro. Furthermore, overexpression of ICER via an adenoviral vector evoked neuronal cell loss in such cultures. The time course of ICER-dependent cell death was hippocampal subdivision specific, with dentate gyrus neurons dying mostly 3-7 days after the adenovector infection, followed by CA3, where neuronal death peaked after 7 days, and then CA1, where most neuronal death occurred after 7-14 days. These results underscore the usefulness of the organotypic cultures for studies of neurodegeneration and point to neuronal loss having a multifaceted nature in a complex cellular environment.