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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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Neurophysiology of acute hippocampal slices: Intracellular recordings. (a-c) EPO enhances inhibitory transmission. (a) Representative recordings of spontaneous, pharmacologically isolated inhibitory postsynaptic currents (sIPSCs) from CA1 neurons. (b) Averaged amplitude of sIPSCs is not significantly altered in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice; P = 0.0869). (c) Averaged frequency of sIPSCs is significantly enhanced in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice). (d-f) EPO decreases excitatory transmission. (d) Representative recordings of spontaneous, pharmacologically isolated excitatory postsynaptic currents (sEPSCs) from CA1 neurons. (e) Averaged amplitude of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice). (f) averaged frequency of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice).
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Figure 4: Neurophysiology of acute hippocampal slices: Intracellular recordings. (a-c) EPO enhances inhibitory transmission. (a) Representative recordings of spontaneous, pharmacologically isolated inhibitory postsynaptic currents (sIPSCs) from CA1 neurons. (b) Averaged amplitude of sIPSCs is not significantly altered in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice; P = 0.0869). (c) Averaged frequency of sIPSCs is significantly enhanced in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice). (d-f) EPO decreases excitatory transmission. (d) Representative recordings of spontaneous, pharmacologically isolated excitatory postsynaptic currents (sEPSCs) from CA1 neurons. (e) Averaged amplitude of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice). (f) averaged frequency of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice).

Mentions: To study cellular mechanisms of EPO action, we performed whole-cell patch-clamp recordings on CA1 pyramidal neurons in acute hippocampal slices from mice at 1 week after the last injection (Figure 1, Exp. 4; Figure 4a–f). Compared to control mice, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons of EPO mice was increased, while the amplitude of sIPSCs was unchanged (Figure 4b, c). In contrast, EPO led to a significant decrease of both amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in CA1 pyramidal neurons (Figure 4e, f). Importantly, there were no significant differences in input resistance or basic noise level between neurons of control and EPO mice (data not shown). Thus, EPO modulates inhibitory and excitatory synaptic transmission inversely.


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)

Neurophysiology of acute hippocampal slices: Intracellular recordings. (a-c) EPO enhances inhibitory transmission. (a) Representative recordings of spontaneous, pharmacologically isolated inhibitory postsynaptic currents (sIPSCs) from CA1 neurons. (b) Averaged amplitude of sIPSCs is not significantly altered in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice; P = 0.0869). (c) Averaged frequency of sIPSCs is significantly enhanced in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice). (d-f) EPO decreases excitatory transmission. (d) Representative recordings of spontaneous, pharmacologically isolated excitatory postsynaptic currents (sEPSCs) from CA1 neurons. (e) Averaged amplitude of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice). (f) averaged frequency of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Neurophysiology of acute hippocampal slices: Intracellular recordings. (a-c) EPO enhances inhibitory transmission. (a) Representative recordings of spontaneous, pharmacologically isolated inhibitory postsynaptic currents (sIPSCs) from CA1 neurons. (b) Averaged amplitude of sIPSCs is not significantly altered in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice; P = 0.0869). (c) Averaged frequency of sIPSCs is significantly enhanced in EPO-treated mice (N = 6 neurons/5 mice) compared to control (N = 4 neurons/4 mice). (d-f) EPO decreases excitatory transmission. (d) Representative recordings of spontaneous, pharmacologically isolated excitatory postsynaptic currents (sEPSCs) from CA1 neurons. (e) Averaged amplitude of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice). (f) averaged frequency of sEPSCs is significantly decreased in EPO-treated mice (N = 4 neurons/4 mice) compared to control (N = 4 neurons/3 mice).
Mentions: To study cellular mechanisms of EPO action, we performed whole-cell patch-clamp recordings on CA1 pyramidal neurons in acute hippocampal slices from mice at 1 week after the last injection (Figure 1, Exp. 4; Figure 4a–f). Compared to control mice, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons of EPO mice was increased, while the amplitude of sIPSCs was unchanged (Figure 4b, c). In contrast, EPO led to a significant decrease of both amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in CA1 pyramidal neurons (Figure 4e, f). Importantly, there were no significant differences in input resistance or basic noise level between neurons of control and EPO mice (data not shown). Thus, EPO modulates inhibitory and excitatory synaptic transmission inversely.

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