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Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.

Stein ES, Itsekson-Hayosh Z, Aronovich A, Reisner Y, Bushi D, Pick CG, Tanne D, Chapman J, Vlachos A, Maggio N - Sci Rep (2015)

Bottom Line: Upon OGD, thrombin activity increased in hippocampal slices.A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP.Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.

ABSTRACT
Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke.

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Related in: MedlinePlus

OGD induces iLTP and increases thrombin activity and protein levels in acute hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP in the hippocampus which is blocked by previous application of 50 μM of APV, an NMDAR antagonist (b). Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. In hippocampal slices undergoing OGD, (c) thrombin activity and (d) concentration are enhanced, while (e) prothrombin mRNA is reduced 10 minutes upon OGD recovery. * p < 0.05; ** p < 0.01.
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f1: OGD induces iLTP and increases thrombin activity and protein levels in acute hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP in the hippocampus which is blocked by previous application of 50 μM of APV, an NMDAR antagonist (b). Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. In hippocampal slices undergoing OGD, (c) thrombin activity and (d) concentration are enhanced, while (e) prothrombin mRNA is reduced 10 minutes upon OGD recovery. * p < 0.05; ** p < 0.01.

Mentions: A brief (3 minutes) episode of in vitro OGD caused a transient reduction in EPSP slopes recorded in stratum radiatum of hippocampal area CA1 (Fig.1a). This was followed by a long-term increase of EPSP slope (up to 1.62 ± 0.078 at 10 minutes after recovery, n = 12 slices; Fig. 1A), reflecting ischemic LTP (iLTP) of excitatory synaptic transmission524. This form of synaptic plasticity requires NMDAR activation21, and hence was blocked in presence of the NMDAR antagonist APV (50 μM; 1.05 ± 0.084 at 10 minutes after recovery, n = 12; p < 0.001; Fig. 1b).


Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.

Stein ES, Itsekson-Hayosh Z, Aronovich A, Reisner Y, Bushi D, Pick CG, Tanne D, Chapman J, Vlachos A, Maggio N - Sci Rep (2015)

OGD induces iLTP and increases thrombin activity and protein levels in acute hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP in the hippocampus which is blocked by previous application of 50 μM of APV, an NMDAR antagonist (b). Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. In hippocampal slices undergoing OGD, (c) thrombin activity and (d) concentration are enhanced, while (e) prothrombin mRNA is reduced 10 minutes upon OGD recovery. * p < 0.05; ** p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300504&req=5

f1: OGD induces iLTP and increases thrombin activity and protein levels in acute hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP in the hippocampus which is blocked by previous application of 50 μM of APV, an NMDAR antagonist (b). Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. In hippocampal slices undergoing OGD, (c) thrombin activity and (d) concentration are enhanced, while (e) prothrombin mRNA is reduced 10 minutes upon OGD recovery. * p < 0.05; ** p < 0.01.
Mentions: A brief (3 minutes) episode of in vitro OGD caused a transient reduction in EPSP slopes recorded in stratum radiatum of hippocampal area CA1 (Fig.1a). This was followed by a long-term increase of EPSP slope (up to 1.62 ± 0.078 at 10 minutes after recovery, n = 12 slices; Fig. 1A), reflecting ischemic LTP (iLTP) of excitatory synaptic transmission524. This form of synaptic plasticity requires NMDAR activation21, and hence was blocked in presence of the NMDAR antagonist APV (50 μM; 1.05 ± 0.084 at 10 minutes after recovery, n = 12; p < 0.001; Fig. 1b).

Bottom Line: Upon OGD, thrombin activity increased in hippocampal slices.A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP.Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.

ABSTRACT
Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke.

Show MeSH
Related in: MedlinePlus