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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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Autaptic hippocampal neuronal cultures. (a-g) Whole-cell electrophysiological recordings from single hippocampal neurons treated with either EPO (0.3 IU/ml) or control (diluent only) on day 7 and measured from day 9–14. Results indicate a reduction in the amount of primed vesicles without altering efficiency of vesicle fusion and vesicle dynamics. Mean ± S.E.M. presented. N = 40–60. (h) Analysing the number of synaptic boutons upon immunocytochemical staining for synapsin1 revealed an almost identical increase of boutons over time in EPO-treated and control neurons. Performed at 40x. Cumulative distribution over days 9–14. N = 100–120.
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Figure 6: Autaptic hippocampal neuronal cultures. (a-g) Whole-cell electrophysiological recordings from single hippocampal neurons treated with either EPO (0.3 IU/ml) or control (diluent only) on day 7 and measured from day 9–14. Results indicate a reduction in the amount of primed vesicles without altering efficiency of vesicle fusion and vesicle dynamics. Mean ± S.E.M. presented. N = 40–60. (h) Analysing the number of synaptic boutons upon immunocytochemical staining for synapsin1 revealed an almost identical increase of boutons over time in EPO-treated and control neurons. Performed at 40x. Cumulative distribution over days 9–14. N = 100–120.

Mentions: Evoked excitatory postsynaptic current (EPSC) amplitudes in EPO-treated neurons were reduced to about 60% of control (Figure 6a), confirming the data obtained in acute slices (Figure 4e). This EPSC reduction was due to a parallel reduction in pool size of fusion-competent and primed (readily releasable) vesicles, whose release can be triggered by hypertonic solution containing 0.5 M sucrose [33]. EPO neurons showed a drastic reduction in readily releasable pool size to 60% of control (Figure 6b). Vesicular release probability, calculated by dividing the charge transfer during a single EPSC by the charge transfer measured during readily releasable pool release, was not different between control and EPO neurons (P = 0.4116; Figure 6c). To test whether the reduction of neurotransmitter release in EPO neurons can be attributed to a reduction in quantal size, we analysed miniature EPSCs (mEPSC). mEPSC frequency in EPO neurons was reduced to about 50% of control, without changes in mEPSC amplitudes (P = 0.5817; Figure 6d, e). The lack of a difference in NMDA/AMPA ratio indicates a comparable maturation state of cultures (Figure 6f). Using trains of action potentials we estimated the efficiency of Ca2+ triggered release. In general, vesicular release probability closely correlates with depression and steady-state level of EPSC amplitude sizes during high frequency stimulation. We therefore monitored EPSC amplitudes during 50 consecutive action potentials applied at a frequency of 10 Hz. EPO and control neurons showed regular moderate depression of EPSC amplitudes (control: about 38%, N = 60; EPO: depression at the end of train about 35%, N = 60, Figure 6g). Stability of EPSC amplitudes during short-term plasticity, which is due to the quantitative balance between priming of synaptic vesicles and number of vesicles released, was identical in presynaptic terminals of each group.


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)

Autaptic hippocampal neuronal cultures. (a-g) Whole-cell electrophysiological recordings from single hippocampal neurons treated with either EPO (0.3 IU/ml) or control (diluent only) on day 7 and measured from day 9–14. Results indicate a reduction in the amount of primed vesicles without altering efficiency of vesicle fusion and vesicle dynamics. Mean ± S.E.M. presented. N = 40–60. (h) Analysing the number of synaptic boutons upon immunocytochemical staining for synapsin1 revealed an almost identical increase of boutons over time in EPO-treated and control neurons. Performed at 40x. Cumulative distribution over days 9–14. N = 100–120.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Autaptic hippocampal neuronal cultures. (a-g) Whole-cell electrophysiological recordings from single hippocampal neurons treated with either EPO (0.3 IU/ml) or control (diluent only) on day 7 and measured from day 9–14. Results indicate a reduction in the amount of primed vesicles without altering efficiency of vesicle fusion and vesicle dynamics. Mean ± S.E.M. presented. N = 40–60. (h) Analysing the number of synaptic boutons upon immunocytochemical staining for synapsin1 revealed an almost identical increase of boutons over time in EPO-treated and control neurons. Performed at 40x. Cumulative distribution over days 9–14. N = 100–120.
Mentions: Evoked excitatory postsynaptic current (EPSC) amplitudes in EPO-treated neurons were reduced to about 60% of control (Figure 6a), confirming the data obtained in acute slices (Figure 4e). This EPSC reduction was due to a parallel reduction in pool size of fusion-competent and primed (readily releasable) vesicles, whose release can be triggered by hypertonic solution containing 0.5 M sucrose [33]. EPO neurons showed a drastic reduction in readily releasable pool size to 60% of control (Figure 6b). Vesicular release probability, calculated by dividing the charge transfer during a single EPSC by the charge transfer measured during readily releasable pool release, was not different between control and EPO neurons (P = 0.4116; Figure 6c). To test whether the reduction of neurotransmitter release in EPO neurons can be attributed to a reduction in quantal size, we analysed miniature EPSCs (mEPSC). mEPSC frequency in EPO neurons was reduced to about 50% of control, without changes in mEPSC amplitudes (P = 0.5817; Figure 6d, e). The lack of a difference in NMDA/AMPA ratio indicates a comparable maturation state of cultures (Figure 6f). Using trains of action potentials we estimated the efficiency of Ca2+ triggered release. In general, vesicular release probability closely correlates with depression and steady-state level of EPSC amplitude sizes during high frequency stimulation. We therefore monitored EPSC amplitudes during 50 consecutive action potentials applied at a frequency of 10 Hz. EPO and control neurons showed regular moderate depression of EPSC amplitudes (control: about 38%, N = 60; EPO: depression at the end of train about 35%, N = 60, Figure 6g). Stability of EPSC amplitudes during short-term plasticity, which is due to the quantitative balance between priming of synaptic vesicles and number of vesicles released, was identical in presynaptic terminals of each group.

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