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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

Neurophysiology of acute hippocampal slices: Extracellular recordings. (a-b) Input-output relation is not altered at Schaffer collateral-CA1 synapses in EPO-treated mice. (a) Sample recordings at 50% of maximal response (average of four traces) are shown for control and EPO-treated mice. (b) Input-output curve as a measure of baseline excitatory synaptic transmission: fEPSP slope, plotted against the stimulation strength, is not altered in EPO-treated mice compared to control (P = 0.3094). Inset: Half maximal stimulation strengths are not significantly different. (c-d) Paired-pulse facilitation is enhanced in EPO-treated mice. (c) Sample traces are presented. (d) Paired-pulse ratio (fEPSP slope for the second stimulus/fEPSP slope for the first stimulus) at inter-stimulus intervals of 25–150 ms is significantly greater in EPO-treated mice. (e-h) Increased LTP at Schaffer collateral CA1 synapses in EPO-treated mice. (e) Sample traces of responses are shown before and after high frequency stimulation (HFS; 3 × 100 Hz for 1 s each, 20 s interval). (f) Long-term potentiation elicited by HFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time-point 0 represents application of HFS. (g) Magnitude of STP, determined as maximal responses within 1 min after HFS, is significantly greater in EPO-treated mice. (h) Magnitude of LTP, determined as responses between 50 and 60 min after HFS, is significantly greater in EPO-treated mice. (i-l) Increased STD at Schaffer collateral-CA1 synapses in EPO-treated mice. (i) Sample traces of responses are shown before and after low frequency stimulation (LFS; 1 Hz for 900 stimulations). (j) Long-term depression elicited by LFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time 0 represents application of LFS. (k) Magnitude of STD, determined as maximal responses within 1 min after LFS, is significantly greater in EPO-treated mice. (l) Magnitude of LTD, determined as responses between 50 and 60 min after LFS, is not significantly changed in EPO-treated mice (P = 0.0869).
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Figure 3: Neurophysiology of acute hippocampal slices: Extracellular recordings. (a-b) Input-output relation is not altered at Schaffer collateral-CA1 synapses in EPO-treated mice. (a) Sample recordings at 50% of maximal response (average of four traces) are shown for control and EPO-treated mice. (b) Input-output curve as a measure of baseline excitatory synaptic transmission: fEPSP slope, plotted against the stimulation strength, is not altered in EPO-treated mice compared to control (P = 0.3094). Inset: Half maximal stimulation strengths are not significantly different. (c-d) Paired-pulse facilitation is enhanced in EPO-treated mice. (c) Sample traces are presented. (d) Paired-pulse ratio (fEPSP slope for the second stimulus/fEPSP slope for the first stimulus) at inter-stimulus intervals of 25–150 ms is significantly greater in EPO-treated mice. (e-h) Increased LTP at Schaffer collateral CA1 synapses in EPO-treated mice. (e) Sample traces of responses are shown before and after high frequency stimulation (HFS; 3 × 100 Hz for 1 s each, 20 s interval). (f) Long-term potentiation elicited by HFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time-point 0 represents application of HFS. (g) Magnitude of STP, determined as maximal responses within 1 min after HFS, is significantly greater in EPO-treated mice. (h) Magnitude of LTP, determined as responses between 50 and 60 min after HFS, is significantly greater in EPO-treated mice. (i-l) Increased STD at Schaffer collateral-CA1 synapses in EPO-treated mice. (i) Sample traces of responses are shown before and after low frequency stimulation (LFS; 1 Hz for 900 stimulations). (j) Long-term depression elicited by LFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time 0 represents application of LFS. (k) Magnitude of STD, determined as maximal responses within 1 min after LFS, is significantly greater in EPO-treated mice. (l) Magnitude of LTD, determined as responses between 50 and 60 min after LFS, is not significantly changed in EPO-treated mice (P = 0.0869).

Mentions: One likely explanation for the selective improvement of contextual memory would be a direct influence of EPO on synaptic plasticity in the hippocampus. We therefore investigated the effect of EPO in acute hippocampal slices from mice at 1 week after the last injection (Figure 1, Exp. 4). We first performed extra-cellular recordings of field excitatory postsynaptic potentials (fEPSPs). Input-output curves were obtained by evoking responses from stratum radiatum of the CA1 region after stimulation of Schaffer collaterals with increasing stimulation strengths (Figure 3a, b). Average of fEPSP slopes (Figure 3b) between stimulus intensities of 110–150 μA from all slices yielded no difference between control and EPO groups. Half-maximal stimulation strength was also comparable (Figure 3b, inset). Thus, EPO treatment for 3 weeks, followed by a treatment-free week, does not alter basal excitability.


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: Extracellular recordings. (a-b) Input-output relation is not altered at Schaffer collateral-CA1 synapses in EPO-treated mice. (a) Sample recordings at 50% of maximal response (average of four traces) are shown for control and EPO-treated mice. (b) Input-output curve as a measure of baseline excitatory synaptic transmission: fEPSP slope, plotted against the stimulation strength, is not altered in EPO-treated mice compared to control (P = 0.3094). Inset: Half maximal stimulation strengths are not significantly different. (c-d) Paired-pulse facilitation is enhanced in EPO-treated mice. (c) Sample traces are presented. (d) Paired-pulse ratio (fEPSP slope for the second stimulus/fEPSP slope for the first stimulus) at inter-stimulus intervals of 25–150 ms is significantly greater in EPO-treated mice. (e-h) Increased LTP at Schaffer collateral CA1 synapses in EPO-treated mice. (e) Sample traces of responses are shown before and after high frequency stimulation (HFS; 3 × 100 Hz for 1 s each, 20 s interval). (f) Long-term potentiation elicited by HFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time-point 0 represents application of HFS. (g) Magnitude of STP, determined as maximal responses within 1 min after HFS, is significantly greater in EPO-treated mice. (h) Magnitude of LTP, determined as responses between 50 and 60 min after HFS, is significantly greater in EPO-treated mice. (i-l) Increased STD at Schaffer collateral-CA1 synapses in EPO-treated mice. (i) Sample traces of responses are shown before and after low frequency stimulation (LFS; 1 Hz for 900 stimulations). (j) Long-term depression elicited by LFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time 0 represents application of LFS. (k) Magnitude of STD, determined as maximal responses within 1 min after LFS, is significantly greater in EPO-treated mice. (l) Magnitude of LTD, determined as responses between 50 and 60 min after LFS, is not significantly changed in EPO-treated mice (P = 0.0869).
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Figure 3: Neurophysiology of acute hippocampal slices: Extracellular recordings. (a-b) Input-output relation is not altered at Schaffer collateral-CA1 synapses in EPO-treated mice. (a) Sample recordings at 50% of maximal response (average of four traces) are shown for control and EPO-treated mice. (b) Input-output curve as a measure of baseline excitatory synaptic transmission: fEPSP slope, plotted against the stimulation strength, is not altered in EPO-treated mice compared to control (P = 0.3094). Inset: Half maximal stimulation strengths are not significantly different. (c-d) Paired-pulse facilitation is enhanced in EPO-treated mice. (c) Sample traces are presented. (d) Paired-pulse ratio (fEPSP slope for the second stimulus/fEPSP slope for the first stimulus) at inter-stimulus intervals of 25–150 ms is significantly greater in EPO-treated mice. (e-h) Increased LTP at Schaffer collateral CA1 synapses in EPO-treated mice. (e) Sample traces of responses are shown before and after high frequency stimulation (HFS; 3 × 100 Hz for 1 s each, 20 s interval). (f) Long-term potentiation elicited by HFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time-point 0 represents application of HFS. (g) Magnitude of STP, determined as maximal responses within 1 min after HFS, is significantly greater in EPO-treated mice. (h) Magnitude of LTP, determined as responses between 50 and 60 min after HFS, is significantly greater in EPO-treated mice. (i-l) Increased STD at Schaffer collateral-CA1 synapses in EPO-treated mice. (i) Sample traces of responses are shown before and after low frequency stimulation (LFS; 1 Hz for 900 stimulations). (j) Long-term depression elicited by LFS: Slopes of fEPSP are normalized to baseline and plotted against time. Time 0 represents application of LFS. (k) Magnitude of STD, determined as maximal responses within 1 min after LFS, is significantly greater in EPO-treated mice. (l) Magnitude of LTD, determined as responses between 50 and 60 min after LFS, is not significantly changed in EPO-treated mice (P = 0.0869).
Mentions: One likely explanation for the selective improvement of contextual memory would be a direct influence of EPO on synaptic plasticity in the hippocampus. We therefore investigated the effect of EPO in acute hippocampal slices from mice at 1 week after the last injection (Figure 1, Exp. 4). We first performed extra-cellular recordings of field excitatory postsynaptic potentials (fEPSPs). Input-output curves were obtained by evoking responses from stratum radiatum of the CA1 region after stimulation of Schaffer collaterals with increasing stimulation strengths (Figure 3a, b). Average of fEPSP slopes (Figure 3b) between stimulus intensities of 110–150 μA from all slices yielded no difference between control and EPO groups. Half-maximal stimulation strength was also comparable (Figure 3b, inset). Thus, EPO treatment for 3 weeks, followed by a treatment-free week, does not alter basal excitability.

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