Regional health and function in the hippocampus: Evolutionary compromises for a critical brain region

The hippocampus is especially vulnerable to damage caused by metabolic dysregulation. However distinct sub-regions within the hippocampus differ by their relative susceptibility to such damage. Region CA1 pyramidal neurons are most sensitive to metabolic perturbations while region CA3 pyramidal neurons show more resistance, and these unique profiles of susceptibility are but one example that differentiates CA1/CA3 neurons. We present here a hypothesis that inextricably links the unique biochemistries of learning and memory in region CA1, to that of cell survival signaling, and in so doing, suggest an explanation for region CA1 susceptibility to metabolic dysfunction. Further, we propose a signaling mechanism to explain how both pathways can be simultaneously regulated. Critical to this process is the protein phosphatase PHLPP1. Finally we discuss the implications of this hypothesis and the inherent challenges it poses for treatment of neurological disorders resulting in reduced hippocampal function by increased neuron death.