Insulin signaling pathways in the brain regulate food uptake and memory and learning.
Insulin and
protein kinase C (PKC) pathways are integrated and function closely together. PKC activation in the brain is essential for learning and neuronal repair. Intranasal delivery of
insulin to the central nervous system (CNS) has been shown to improve memory, reduce cerebral
atrophy, and reverse neurodegeneration. However, the neuronal molecular mechanisms of these effects have not been studied in depth. PKCδ plays a central role in cell survival. Its splice variants, PKCδI and PKCδII, are switches that determine cell survival and fate. PKCδI promotes apoptosis, whereas PKCδII promotes survival. Here, we demonstrate that
insulin promotes alternative splicing of PKCδII
isoform in HT22 cells. The expression of PKCδI splice variant remains unchanged.
Insulin increases PKCδII alternative splicing via the PI3K pathway. We further demonstrate that Akt
kinase mediates phosphorylation of the
splicing factor SC35 to promote PKCδII alternative splicing. Using overexpression and knockdown assays, we demonstrate that
insulin increases expression of Bcl2 and bcl-xL via PKCδII. We demonstrate increased cell proliferation and increased
BrdU incorporation in
insulin-treated cells as well as in HT22 cells overexpressing PKCδII. Finally, we demonstrate in vivo that intranasal
insulin promotes cognitive function in mice with concomitant increases in PKCδII expression in the hippocampus. This is the first report of
insulin, generally considered a growth or metabolic
hormone, regulating the alternative
isoform expression of a key signaling
kinase in neuronal cells such that it results in increased neuronal survival.