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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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Thrombin induces iLTP.Upon ischemia, the increased thrombin activity leads to the activation of PAR1 and NMDARs thus causing iLTP.
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f5: Thrombin induces iLTP.Upon ischemia, the increased thrombin activity leads to the activation of PAR1 and NMDARs thus causing iLTP.

Mentions: In this manuscript, we investigated the role of thrombin in synaptic plasticity following OGD. Using an in vitro model of acute ischemia, we were able to demonstrate that thrombin activity, which is enhanced upon OGD in vitro, induces iLTP through the activation of PAR1 and NMDARs (Fig.5). Strikingly, blockade of thrombin and PAR1 signaling inhibited iLTP and restored the ability of neurons to express physiological synaptic plasticity following OGD.


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)

Thrombin induces iLTP.Upon ischemia, the increased thrombin activity leads to the activation of PAR1 and NMDARs thus causing iLTP.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Thrombin induces iLTP.Upon ischemia, the increased thrombin activity leads to the activation of PAR1 and NMDARs thus causing iLTP.
Mentions: In this manuscript, we investigated the role of thrombin in synaptic plasticity following OGD. Using an in vitro model of acute ischemia, we were able to demonstrate that thrombin activity, which is enhanced upon OGD in vitro, induces iLTP through the activation of PAR1 and NMDARs (Fig.5). Strikingly, blockade of thrombin and PAR1 signaling inhibited iLTP and restored the ability of neurons to express physiological synaptic plasticity following OGD.

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