Erythropoietin enhances postnatal hippocampal mitochondrial content, function, and cognition

Abstract It is increasingly evident that mitochondria are crucial in regulating neurodevelopment, brain function and cognition. Erythropoietin (EPO) has been shown to improve mitochondrial function and cognition following brain damage and in patients with neurological disorders. However, potential EPO-mediated influence(s) on hippocampal mitochondrial function during postnatal development and it corresponds to enhanced cognition is unknown. Here we show in mice, that EPO receptors (EpoR)s express postnatally in the CA1 pyramidal cells of the hippocampus reaching a zenith at puberty (postnatal (P) age 21). Constitutive neuronal EPO overexpression increases hippocampal Erk1/2 and AKT phosphorylation along with increases in cellular respiration and mitochondrial content by the third postnatal week of development. Indices of cellular oxidant balance do not appear altered by higher respiratory potentials and greater mitochondrial content. Finally, EPO overexpression also enhances hippocampal-dependent learning and memory at early adulthood (P60). Collectively, this data identifies a novel function for EPO signaling, promoting improvements in hippocampal-specific mitochondrial function and cognition during postnatal development and early adulthood.