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Erythropoietin enhances hippocampal long-term potentiation and memory.

Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, Zhang M, Müller M, Hassouna I, Hannke K, Sperling S, Radyushkin K, El-Kordi A, Schulze L, Ronnenberg A, Wolf F, Brose N, Rhee JS, Zhang W, Ehrenreich H - BMC Biol. (2008)

Bottom Line: 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.We 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. adamcio@em.mpg.de

ABSTRACT

Background: Erythropoietin (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.

Results: We 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.

Conclusion: We 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.

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Related in: MedlinePlus

Effects of EPO on hippocampus dependent memory. Percentage of freezing as a readout of memory function in fear conditioning shows significant effects upon EPO treatment in the contextual memory (context) task at 1 week (a) and 3 weeks (b), but no longer at 4 weeks (c) after the last EPO injection. Percentage of freezing measured during training (baseline), exposition to the new context (pre-cue), and testing for cued memory (cue) is not different between the groups. No differences are seen in EPM (d), OF (e), HB (f), and RR (g). Mean ± S.E.M. N = 28 for experiment in (a) and N = 14 for all other experiments (b-g).
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Figure 2: Effects of EPO on hippocampus dependent memory. Percentage of freezing as a readout of memory function in fear conditioning shows significant effects upon EPO treatment in the contextual memory (context) task at 1 week (a) and 3 weeks (b), but no longer at 4 weeks (c) after the last EPO injection. Percentage of freezing measured during training (baseline), exposition to the new context (pre-cue), and testing for cued memory (cue) is not different between the groups. No differences are seen in EPM (d), OF (e), HB (f), and RR (g). Mean ± S.E.M. N = 28 for experiment in (a) and N = 14 for all other experiments (b-g).

Mentions: First goal of this study was to define an experimental condition to test potential abilities of EPO to improve cognitive functions. We used young (28 day old) male mice. In our experimental set-up with 11 intra-peritoneal EPO versus placebo injections (5000 IU/kg) every other day for 3 weeks (Figure 1), EPO-treated mice showed significant improvement of contextual memory in fear conditioning 1 week after the last injection, when tested 72 h after training in the same context (Figure 1, Exp. 1, Figure 2a). This effect was still measurable 3 weeks after cessation of EPO treatment but had disappeared after 4 weeks (Figure 1, Exp. 2 and Exp. 3; Figure 2b, c). In contrast, EPO had no effect on cued memory (Figure 2a–c; all P > 0.05). Whereas at 1 week after termination of treatment, hematocrit was still increased in EPO-treated mice (control mice: 36.5 ± 0.84%, N = 8; EPO mice: 53.3 ± 1.34%, N = 10; P < 0.0001), there was no difference anymore between groups at 3 weeks (control mice: 39.4 ± 1.19%, N = 14; EPO mice: 40.8 ± 0.92%, N = 13; P = 0.338), indicating that cognitive improvement and hematopoietic effects of EPO are not directly related.


Erythropoietin enhances hippocampal long-term potentiation and memory.

Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, Zhang M, Müller M, Hassouna I, Hannke K, Sperling S, Radyushkin K, El-Kordi A, Schulze L, Ronnenberg A, Wolf F, Brose N, Rhee JS, Zhang W, Ehrenreich H - BMC Biol. (2008)

Effects of EPO on hippocampus dependent memory. Percentage of freezing as a readout of memory function in fear conditioning shows significant effects upon EPO treatment in the contextual memory (context) task at 1 week (a) and 3 weeks (b), but no longer at 4 weeks (c) after the last EPO injection. Percentage of freezing measured during training (baseline), exposition to the new context (pre-cue), and testing for cued memory (cue) is not different between the groups. No differences are seen in EPM (d), OF (e), HB (f), and RR (g). Mean ± S.E.M. N = 28 for experiment in (a) and N = 14 for all other experiments (b-g).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2562991&req=5

Figure 2: Effects of EPO on hippocampus dependent memory. Percentage of freezing as a readout of memory function in fear conditioning shows significant effects upon EPO treatment in the contextual memory (context) task at 1 week (a) and 3 weeks (b), but no longer at 4 weeks (c) after the last EPO injection. Percentage of freezing measured during training (baseline), exposition to the new context (pre-cue), and testing for cued memory (cue) is not different between the groups. No differences are seen in EPM (d), OF (e), HB (f), and RR (g). Mean ± S.E.M. N = 28 for experiment in (a) and N = 14 for all other experiments (b-g).
Mentions: First goal of this study was to define an experimental condition to test potential abilities of EPO to improve cognitive functions. We used young (28 day old) male mice. In our experimental set-up with 11 intra-peritoneal EPO versus placebo injections (5000 IU/kg) every other day for 3 weeks (Figure 1), EPO-treated mice showed significant improvement of contextual memory in fear conditioning 1 week after the last injection, when tested 72 h after training in the same context (Figure 1, Exp. 1, Figure 2a). This effect was still measurable 3 weeks after cessation of EPO treatment but had disappeared after 4 weeks (Figure 1, Exp. 2 and Exp. 3; Figure 2b, c). In contrast, EPO had no effect on cued memory (Figure 2a–c; all P > 0.05). Whereas at 1 week after termination of treatment, hematocrit was still increased in EPO-treated mice (control mice: 36.5 ± 0.84%, N = 8; EPO mice: 53.3 ± 1.34%, N = 10; P < 0.0001), there was no difference anymore between groups at 3 weeks (control mice: 39.4 ± 1.19%, N = 14; EPO mice: 40.8 ± 0.92%, N = 13; P = 0.338), indicating that cognitive improvement and hematopoietic effects of EPO are not directly related.

Bottom Line: 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.We 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany. adamcio@em.mpg.de

ABSTRACT

Background: Erythropoietin (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.

Results: We 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.

Conclusion: We 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.

Show MeSH
Related in: MedlinePlus