Insulin signaling activation protects dentate neurons from oxygen‐glucose deprivation in organotypic hippocampal slice cultures

Abstract

A link between diabetes and ischemia has been well accepted. However, the physiological and pathophysiological roles of insulin in the brain are not fully understood. In the present study, we used organotypic hippocampal slice cultures as an in vitro model to study the role of insulin signaling in cell survival/death in oxygen‐glucose deprivation (OGD)‐induced injury. We found that, as compared to the CA1‐3 regions, the dentate gyrus (DG) neuronal survival was more sensitive to inhibition of PI3K/AKt signaling under basal conditions. Dentate neuronal sensitivity to PI3K/Akt signaling activation was inversely related to their vulnerability to OGD‐induced injury. Insulin conferred neuroprotection to DG neurons via activation of PI3K/Akt signaling. In contrast, CA1 and CA3 neurons were less sensitive to PI3K/Akt signaling but more vulnerable to OGD. MAPK inhibitors reduced CA neuronal injury from OGD when PI3K signaling was inhibited. In addition, in the presence of insulin, CA1 neurons were partly protected from OGD by these MAPK inhibitors, and were also protected by NMDA receptor blocker CPP, suggesting that an activity‐dependent activation of MAPK signaling may contribute to CA1 neuronal vulnerability. CA2 sub‐region was distinctive in its response to glutamate, OGD, and insulin, compared to other CA sub‐regions. CA2 neurons were sensitive to the protective effects of insulin from OGD, but more resistant to those of glutamate. Our results suggest that PI3K and MAPK mediated survival/death signaling may play a role in sub‐regional vulnerability to cerebral ischemia. We speculate that activation of insulin signaling pathways contributes to neuronal repair under pathophysiological conditions such as diabetes and stroke.