Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging

Distinct neuronal populations differ by the degree of damage caused from cellular stress. Hippocampal neurons of area CA1 are especially vulnerable to several stressors that increase as age advances. We show here that survival signaling, as measured by activated protein kinase B (AKT), was significantly reduced in the nuclear CA1 region across the lifespan compared with CA3. In agreement with these findings, the pro-apoptotic protein and AKT nuclear substrate, forkhead box O3a transcription factor (FOXO3a), were significantly higher in CA1. Further, regional differences in PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), a recently discovered inhibitor of AKT, inversely correlated with nuclear phosphorylated AKT at Ser473. Altogether, our data suggest that regional differences in nuclear levels of activated AKT may contribute to regional differences in hippocampal vulnerability and implicate PHLPP1 as a potential target for therapeutic intervention to improve hippocampal health.