ISCHEMIA-INDUCED CA1 NEURONAL DEATH IS PRECEDED BY ELEVATED FOSB AND JUN EXPRESSION AND REDUCED NGFI-A AND JUNB LEVELS

Alterations in levels of the immediate-early gene (IEG) proteins Fos, FosB, Delta FosB, Jun, JunB, JunD, and NGFI-A were investigated in rat hippocampus by immunohistochemistry 2, 12, 24, and 48 h after forebra in ischemia. Transient global ischemia of 20 min, produced by four ves sel occlusion (4-VO), elicited different patterns of LEG expression in vulnerable CA1 and more resilient CA3 neurons. Cell counts revealed t hat except for JunD and NGFI-A, immunoreactivity for all examined IEGs was initially elevated by forebrain ischemia in both CA1 and CA3 hipp ocampal subfields. However, distinct patterns of IEG expression became evident in these regions at later time points. The pivotal difference was the persistence of ischemia-induced elevations of FosB and Jun ex pression in the CA1 region of the hippocampus. Unlike CA3 neurons, whe re IEG immunoreactivity had subsided to basal levels by 24-48 h, CA1 n eurons continued to display increased FosB- and Jun-Like immunoreactiv ity 48 h post-ischemia. Western blot analysis revealed that elevated e xpression of both FosB and Delta FosB-like proteins were responsible f or the immunohistochemical detection of enhanced FosB-like immunoreact ivity in CA1 neurons at 48 h. These findings are consistent with recen t in vitro studies that implicate FosB and Jun in gene signalling path ways responsible for programmed cell death. In contrast to FosB and Ju n, JunB expression declined significantly below basal levels in CA1 ne urons at 48 h, yet remained unaltered in CA3 neurons. Given that JunB can inhibit the transactivating properties of Jun, decreased JunB leve ls may contribute to the apoptotic death of CA1 neurons by enhancing t he transcriptional regulating activity of Jun. Also notable at 48 h wa s the complete loss of constitutive NGFI-A expression from CA1 neurons of ischemic animals. These findings suggest that persistent elevation s in FosB and Jun expression, concurrent with reductions in JunB and N GFI-A levels, contribute to the apoptotic death of CA1 neurons after f orebrain ischemia. (C) 1998 Elsevier Science B.V.