Abstract
Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood.
Highlights
Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders
Murine EPO expression was hardly detected in the brain of WT and Tg21 mice while recombinant human EPO (rhEPO) was only detected in the brain of Tg21 mice (2-way ANOVA, F(1,16) = 275, p < 0.0001; Supplementary Fig. 1b)
Constitutive overexpression of rhEPO was restricted to the brain of Tg21 groups (P5 and P21) (1-way ANOVA brain, F(2,9) = 30.57, p < 0.0001) with a minor transient elevation detected in the liver at P5 but no differences in kidney or spleen (Supplementary Fig. 1c)
Summary
Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. We identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood. EPO prevents hippocampal neurodegeneration and attendant cognitive impairment in rodents presenting with diabetes[9] or Alzheimerlike diseases[10,11] as well as reduces long-term spatial-memory deficits across various animal models of neonatal brain injury[12,13]. EPO has been reported to support neuronal mitochondria and prevent memory impairment in animal models of multiple sclerosis, sleep deprivation, neurodegeneration, and brain injury[32,33,34,35,36]. We have recently reported that EPO signals on CA1 pyramidal cells in the hippocampus and improves hippocampal postnatal neuronal maturation by reducing cell death and promoting synaptogenesis[39].
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