Regional specific activations of ERK1/2 and CDK5 differently regulate astroglial responses to ER stress in the rat hippocampus following status epilepticus

Abstract

Endoplasmic reticulum (ER) triggers the regional specific astroglial responses to status epilepticus (SE, a prolonged seizure activity). However, the epiphenomena/downstream effecters for ER stress and the mechanism of ER stress signaling in astroglial apoptosis have not been fully understood. In the present study, tunicamycin-induced ER stress resulted in reactive astrogliosis-like events showing astroglial hypertrophy with the elevated extracellular signal-activated protein kinase 1/2 (ERK1/2) and cyclin-dependent kinase 5 (CDK5) phosphorylations in the CA1 region of the rat hippocampus. However, tunicamycin increased CDK5, but not ERK1/2, phosphorylation in the molecular layer of the dentate gyrus. Roscovitine (a CDK5 inhibitor) suppressed the effect of tunicamycin in the molecular layer of the dentate gyrus and the CA1 region, while U0126 (an ERK1/2 inhibitor) reversed it in the CA1 region. Salubrinal (an ER stress inhibitor) abrogated activations of ERK1/2 and CDK5, and attenuated reactive astrogliosis in the CA1 region and astroglial apoptosis in the molecular layer of the dentate gyrus following status epilepticus (SE, a prolonged seizure activity). These findings indicate that ER stress may induce reactive astrogliosis via ERK1/2-mediated CDK5 activation in the CA1 region. In the molecular layer of the dentate gyrus, however, ER stress may participate in astroglial apoptosis through ERK1/2-independent CDK5 activation following SE.