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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

Multi-electrode array studies of primary hippocampal neurons. (a-b) Characterization of the cultures. (a) Immunocytochemical staining demonstrates maturation of cellular networks from day 10 to day 30. Propidium iodide staining of all nuclei (red), visualization of cell types by MAP-2 (mature neurons) or GFAP (astrocytes) staining (green), as well as merged pictures are presented (scale bar = 100 μm). (b) Cellular composition of networks remains stable over time and is not altered by EPO treatment (0.3 IU/ml every other day) from day 5 through 25 in culture (Mean ± S.E.M. of N = 3 independent cultures per time point). (c) Demonstration of primary hippocampal neurons grown on multi-electrode array dishes, containing 60 electrodes/dish. (d-e) Spontaneous electrical activity of primary hippocampal neuronal networks in culture is measured daily from week 3 through week 7. Group statistics of the multi-electrode array recordings over each week show significant dissociation over time of EPO versus control cultures. (d) Silencing group statistics reveal a global decrease of channels with low activity in control cultures that cannot be observed in EPO-treated cultures. (e) Bursting group statistics show that the percentage of strongly bursting channels increases in the EPO group after termination of treatment. Medians ± S.E.M. presented of N = 7 independent cultures. P values are given in the text.
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Figure 5: Multi-electrode array studies of primary hippocampal neurons. (a-b) Characterization of the cultures. (a) Immunocytochemical staining demonstrates maturation of cellular networks from day 10 to day 30. Propidium iodide staining of all nuclei (red), visualization of cell types by MAP-2 (mature neurons) or GFAP (astrocytes) staining (green), as well as merged pictures are presented (scale bar = 100 μm). (b) Cellular composition of networks remains stable over time and is not altered by EPO treatment (0.3 IU/ml every other day) from day 5 through 25 in culture (Mean ± S.E.M. of N = 3 independent cultures per time point). (c) Demonstration of primary hippocampal neurons grown on multi-electrode array dishes, containing 60 electrodes/dish. (d-e) Spontaneous electrical activity of primary hippocampal neuronal networks in culture is measured daily from week 3 through week 7. Group statistics of the multi-electrode array recordings over each week show significant dissociation over time of EPO versus control cultures. (d) Silencing group statistics reveal a global decrease of channels with low activity in control cultures that cannot be observed in EPO-treated cultures. (e) Bursting group statistics show that the percentage of strongly bursting channels increases in the EPO group after termination of treatment. Medians ± S.E.M. presented of N = 7 independent cultures. P values are given in the text.

Mentions: First, our long-term cultures were characterized regarding morphological appearance (Figure 5a), total cell numbers (day 10: control: 202.4 ± 11.03, N = 6; EPO: 191.0 ± 8.834, N = 6; P = 0.436; day 30: control: 147.9 ± 26.26, N = 6; EPO: 152.8 ± 27.87, N = 6; P = 0.902), and relative contribution of different cell types (Figure 5b). In none of these parameters were differences upon EPO found at days 10 or 30 in culture. Also, quantitative RT PCR and protein expression, determined by Western blotting, failed to uncover differences in synapsin1 or synaptophysin gene expression at any of the time points tested (days 8, 14, and 30). Thus, EPO treatment did not cause changes in morphology under our culture conditions.


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)

Multi-electrode array studies of primary hippocampal neurons. (a-b) Characterization of the cultures. (a) Immunocytochemical staining demonstrates maturation of cellular networks from day 10 to day 30. Propidium iodide staining of all nuclei (red), visualization of cell types by MAP-2 (mature neurons) or GFAP (astrocytes) staining (green), as well as merged pictures are presented (scale bar = 100 μm). (b) Cellular composition of networks remains stable over time and is not altered by EPO treatment (0.3 IU/ml every other day) from day 5 through 25 in culture (Mean ± S.E.M. of N = 3 independent cultures per time point). (c) Demonstration of primary hippocampal neurons grown on multi-electrode array dishes, containing 60 electrodes/dish. (d-e) Spontaneous electrical activity of primary hippocampal neuronal networks in culture is measured daily from week 3 through week 7. Group statistics of the multi-electrode array recordings over each week show significant dissociation over time of EPO versus control cultures. (d) Silencing group statistics reveal a global decrease of channels with low activity in control cultures that cannot be observed in EPO-treated cultures. (e) Bursting group statistics show that the percentage of strongly bursting channels increases in the EPO group after termination of treatment. Medians ± S.E.M. presented of N = 7 independent cultures. P values are given in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Multi-electrode array studies of primary hippocampal neurons. (a-b) Characterization of the cultures. (a) Immunocytochemical staining demonstrates maturation of cellular networks from day 10 to day 30. Propidium iodide staining of all nuclei (red), visualization of cell types by MAP-2 (mature neurons) or GFAP (astrocytes) staining (green), as well as merged pictures are presented (scale bar = 100 μm). (b) Cellular composition of networks remains stable over time and is not altered by EPO treatment (0.3 IU/ml every other day) from day 5 through 25 in culture (Mean ± S.E.M. of N = 3 independent cultures per time point). (c) Demonstration of primary hippocampal neurons grown on multi-electrode array dishes, containing 60 electrodes/dish. (d-e) Spontaneous electrical activity of primary hippocampal neuronal networks in culture is measured daily from week 3 through week 7. Group statistics of the multi-electrode array recordings over each week show significant dissociation over time of EPO versus control cultures. (d) Silencing group statistics reveal a global decrease of channels with low activity in control cultures that cannot be observed in EPO-treated cultures. (e) Bursting group statistics show that the percentage of strongly bursting channels increases in the EPO group after termination of treatment. Medians ± S.E.M. presented of N = 7 independent cultures. P values are given in the text.
Mentions: First, our long-term cultures were characterized regarding morphological appearance (Figure 5a), total cell numbers (day 10: control: 202.4 ± 11.03, N = 6; EPO: 191.0 ± 8.834, N = 6; P = 0.436; day 30: control: 147.9 ± 26.26, N = 6; EPO: 152.8 ± 27.87, N = 6; P = 0.902), and relative contribution of different cell types (Figure 5b). In none of these parameters were differences upon EPO found at days 10 or 30 in culture. Also, quantitative RT PCR and protein expression, determined by Western blotting, failed to uncover differences in synapsin1 or synaptophysin gene expression at any of the time points tested (days 8, 14, and 30). Thus, EPO treatment did not cause changes in morphology under our culture conditions.

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