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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

Blockade of either thrombin or PAR1 fails to induce iLTP in acute hippocampal slices.A brief exposure (3 minutes) to OGD in presence of either (a) 1 μM of the thrombin inhibitor α-NAPAP or (b) 1 μM of the PAR1 antagonist SCH797977 fails to induce iLTP. (c) A brief exposure to OGD (3 minutes) fails to induce iLTP in PAR1−/− mice. Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section.
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f2: Blockade of either thrombin or PAR1 fails to induce iLTP in acute hippocampal slices.A brief exposure (3 minutes) to OGD in presence of either (a) 1 μM of the thrombin inhibitor α-NAPAP or (b) 1 μM of the PAR1 antagonist SCH797977 fails to induce iLTP. (c) A brief exposure to OGD (3 minutes) fails to induce iLTP in PAR1−/− mice. Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section.

Mentions: In order to assess whether thrombin is involved in iLTP induction, OGD experiments were repeated in the presence of the specific thrombin inhibitor α-NAPAP (1 μM)1225. Indeed, iLTP was impaired in these experiments: EPSP slopes were 1.10 ± 0.06 at 10 minutes following OGD recovery compared to 0.97 ± 0.05 at the baseline (n = 12; P = 0.52; Fig.2a).


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)

Blockade of either thrombin or PAR1 fails to induce iLTP in acute hippocampal slices.A brief exposure (3 minutes) to OGD in presence of either (a) 1 μM of the thrombin inhibitor α-NAPAP or (b) 1 μM of the PAR1 antagonist SCH797977 fails to induce iLTP. (c) A brief exposure to OGD (3 minutes) fails to induce iLTP in PAR1−/− mice. Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Blockade of either thrombin or PAR1 fails to induce iLTP in acute hippocampal slices.A brief exposure (3 minutes) to OGD in presence of either (a) 1 μM of the thrombin inhibitor α-NAPAP or (b) 1 μM of the PAR1 antagonist SCH797977 fails to induce iLTP. (c) A brief exposure to OGD (3 minutes) fails to induce iLTP in PAR1−/− mice. Averaged EPSPs are plotted versus time. Representative traces at indicated times (a, b) are shown for each section.
Mentions: In order to assess whether thrombin is involved in iLTP induction, OGD experiments were repeated in the presence of the specific thrombin inhibitor α-NAPAP (1 μM)1225. Indeed, iLTP was impaired in these experiments: EPSP slopes were 1.10 ± 0.06 at 10 minutes following OGD recovery compared to 0.97 ± 0.05 at the baseline (n = 12; P = 0.52; Fig.2a).

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