Insulin/IGF signaling induces distinctive patterns of histone H3 phosphorylation in hippocampal slice cultures

Position‐specific modifications of the histone H3 have been associated with chromatin‐based transcriptional regulation. Both phosphorylation of histone H3 at Ser 10 (PH3) and insulin/IGF signaling have been implicated in learning and memory. We examined insulin signaling profiles and insulin stimulated PH3 in hippocampal slice cultures. Insulin receptors (β subunit) were abundantly expressed in fiber pathways and co‐localized with the presynaptic marker synapsin. PI3K (p110α) was present in both the nucleus and cytosol, with higher expression detected in cell layers of CA sub‐regions compared to that of the Dentate Gyrus (DG). This was correlated with a higher vulnerability of DG granule neurons to inhibition of endogenous PI3K/Akt, as well as their higher sensitivity to exogenous insulin induced neuroprotection. Insulin/IGF increased PH3‐positive cells in all sub‐regions. Nuclear staining profiles indicated that PH3‐positive cells exhibit variable levels of staining. Proliferative and mitotic cells were intensely stained with a precise correlation between PH3 and chromatin condensation. Inhibitors of MAPK or PI3K, but not actin cytoskeleton, attenuated insulin induced increase in PH3 positive cells. We suggest that the insulin/IGF signaling induced PH3 expression and the associated gene expression and cell proliferation may play a role in neuroprotection after hypoxia/ischemia.