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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., Robert Jacobs, Mostafa Aboouf, et al. examined the effect of erythropoietin (EPO) in hippocampal mitochondrial function and memory in two mouse models: one overexpressing EPO in the brain, and juvenile mice treated during three days with a high dose of intraperitoneal EPO. Their results suggest that erythropoietin in the neonatal brain may impact spatial memory by increasing mitochondrial content.

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.

Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has recently been shown to act as a neurotrophic factor to control the development of area postrema → nucleus of the solitary tract and arcuate hypothalamic nucleus → paraventricular nucleus axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. For investigation of the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR), was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue. Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.

Several neurodevelopmental disabilities are strongly associated with alterations in GABAergic transmission, and therapies to stimulate its normal development are lacking. Erythropoietin (EPO) is clinically used in neonatology to mitigate acute brain injury, and to stimulate neuronal maturation. Yet it remains unclear whether EPO can stimulate maturation of the GABAergic system. Here, with the use of a transgenic mouse line that constitutively overexpresses neuronal EPO (Tg21), we show that EPO stimulates postnatal GABAergic maturation in the hippocampus. We show an increase in hippocampal GABA-immunoreactive neurons, and postnatal elevation of interneurons expressing parvalbumin (PV), somatostatin (SST), and neuropeptide Y (NPY). Analysis of perineuronal net (PNN) formation and innervation of glutamatergic terminals onto PV+ cells, shows to be enhanced early in postnatal development. Additionally, an increase in GABAAergic synapse density and IPSCs in CA1 pyramidal cells from Tg21 mice is observed. Detection of EPO receptor (EPOR) mRNA was observed to be restricted to glutamatergic pyramidal cells and increased in Tg21 mice at postnatal day (P)7, along with reduced apoptosis. Our findings show that EPO can stimulate postnatal GABAergic maturation in the hippocampus, by increasing neuronal survival, modulating critical plasticity periods, and increasing synaptic transmission. Our data supports EPO’s clinical use to balance GABAergic dysfunction., eNeuro, 8 (1), ISSN:2373-2822

Exposure to hypobaric hypoxia at high altitude (above 2500 m asl) causes cognitive impairment, mostly attributed to changes in brain perfusion and consequently neuronal death. Enriched environment and voluntary exercise has been shown to improve cognitive function, to enhance brain microvasculature and neurogenesis, and to be neuroprotective. Here we show that high-altitude exposure (3540 m asl) of Long Evans rats during early adulthood (P48-P59) increases brain microvasculature and neurogenesis but impairs spatial and visual memory along with an increase in neuronal apoptosis. We tested whether enriched environment including a running wheel for voluntary exercise (EE) can prevent cognitive impairment at high-altitude and whether apoptosis is prevented. We found that EE retained spatial and visual memory at high altitude, and prevented neuronal apoptosis. Further, we tested whether vascular endothelial growth factor (VEGF) signaling is required for the EE-mediated recovery of spatial and visual memory and the reduction in apoptosis. Pharmacological inhibition of VEGF signaling by oral application of a tyrosine kinase inhibitor (Vandetanib) prevented the recovery of spatial and visual memory in animals housed in EE, along with an increase in apoptosis and a reduction in neurogenesis. Surprisingly, inhibition of VEGF signaling also caused impairment in spatial memory in EE-housed animals reared at low altitude, affecting mainly dentate gyrus microvasculature but not neurogenesis. We conclude that EE-mediated VEGF signaling is neuroprotective and essential for the maintenance of cognition and neurogenesis during high-altitude exposure, and for the maintenance of spatial memory at low altitude. Finally, our data also underlines the potential risk of cognitive impairment and disturbed high altitude adaption from the use of VEGF-signaling inhibitors for therapeutic purposes. This research was supported by the Swiss National Science Foundation [Marie Heim-Vogtlin (MHV) - SNF grant PMPDP3_145480], the Institute of Veterinary Physiology and the Institute of Pharmacology and Toxicology at the University of Zurich, the Institute of Anatomy at the University of Freiburg, and the Institute of Neuroscience at the University of Basque, Spain.