Erythropoietin enhances hippocampal long-term potentiation and memory

Abstract

BackgroundErythropoietin (EPO) improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity.ResultsWe show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP), a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses.ConclusionWe conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…27 Very recently, we discovered that EPO is able to enhance hippocampal long-term and short-term potentiation and neuronal plasticity, considered prerequisites for learning and memory processes in this brain area. 125 Most intriguingly, we found that EPO prevents the development of slowly progressing global brain atrophy in a mouse model of chronic neurodegeneration. 86 The fact that EPO reduced in vitro haloperidolinduced death of primary hippocampal neurons, further encouraged continuation of our plans to use this compound for treating schizophrenic patients.…”

Effects of Erythropoietin on Memory Deficits and Brain Oxidative Stress in the Mouse Models of Dementia

“…Many studies have also implicated potential anti-oxidative (Genc et al, 2004;Signore et al, 2006;Xue et al, 2007;Wang et al, 2009) actions of EPO. Few recent reports have documented a prominent role of erythropoietin in process of long term-potentiation (LTP) hence memory formation (Adamcio et al, 2008;El-Kordi et al, 2009). Erythropoietin probably exerts its actions via acting as a ligand for erythropoietin receptors and stimulating erythropoietin receptor mediated signaling cascade, which certainly plays a prominent role in process of LTP and memory (Adamcio et al, 2008;El-Kordi et al, 2009).…”

“…Few recent reports have documented a prominent role of erythropoietin in process of long term-potentiation (LTP) hence memory formation (Adamcio et al, 2008;El-Kordi et al, 2009). Erythropoietin probably exerts its actions via acting as a ligand for erythropoietin receptors and stimulating erythropoietin receptor mediated signaling cascade, which certainly plays a prominent role in process of LTP and memory (Adamcio et al, 2008;El-Kordi et al, 2009). Therefore it may be put forth that EPO in our investigation attenuated scopolamine -induced memory deficits and associated biochemical changes by virtue of its multiple actions including anti-oxidative, neuroprotective, and anti-cholinesterase actions.…”

Adult hippocampal neurogenesis and related neurotrophic factors

“…The brains of EPO receptor (EPOR) knockout mice show enhanced apoptosis and the mice are highly sensitive to hypoxia (74), but it is not known if this sensitivity is because EPO has a neuroprotective effect or is a secondary effect of decreased oxygen delivery to the brain. A recent study demonstrates that EPO treatment improves hippocampal-dependent memory by modulating neuronal plasticity and synaptic connectivity, suggesting EPO to be a potential neuropsychiatric drug (75). Image analysis in clinical research has shown that EPO rapidly improves mood and modulates cognitive neural processing, as do serotonergic antidepressant drugs (59).…”