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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

Either thrombin or PAR1 blockade restore physiological tetanus induced LTP in OGD exposed hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP and blocks stimulus onset LTP: a tetanic stimulation to the same pathway, adjusted to submaximal level (downward arrow), is able to produce a short-term but not a long-term potentiation. (b) Blockade of either thrombin or PAR1 through (b) 1 μM α-NAPAP or (c) 1 μM SCH79797 respectively blocks iLTP and restores tetanus induced LTP. Averaged EPSP are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. Upward arrows indicate the time of HFS.
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f4: Either thrombin or PAR1 blockade restore physiological tetanus induced LTP in OGD exposed hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP and blocks stimulus onset LTP: a tetanic stimulation to the same pathway, adjusted to submaximal level (downward arrow), is able to produce a short-term but not a long-term potentiation. (b) Blockade of either thrombin or PAR1 through (b) 1 μM α-NAPAP or (c) 1 μM SCH79797 respectively blocks iLTP and restores tetanus induced LTP. Averaged EPSP are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. Upward arrows indicate the time of HFS.

Mentions: Since iLTP is considered to be a pathological form of synaptic plasticity, which alters the plastic properties of healthy neuronal networks4, we reasoned that physiological, i.e., tetanus-induced LTP will be impaired in a network previously exposed to OGD. In order to test this hypothesis, in a two pathway experimental setting, hippocampal slices were once more exposed to OGD. This resulted in iLTP at both pathways recorded in parallel (Fig. 4a). When potentiation levels reached saturation, the stimulation intensity at one pathway was reduced to the level of baseline and a tetanic stimulation (100 Hz; 1 second) was then delivered at this pathway. Strikingly, the tetanus did not evoke LTP (0.993 ± 0.06 at 25 minutes after tetanic stimulation, n = 12, Fig. 4a) under these conditions.


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)

Either thrombin or PAR1 blockade restore physiological tetanus induced LTP in OGD exposed hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP and blocks stimulus onset LTP: a tetanic stimulation to the same pathway, adjusted to submaximal level (downward arrow), is able to produce a short-term but not a long-term potentiation. (b) Blockade of either thrombin or PAR1 through (b) 1 μM α-NAPAP or (c) 1 μM SCH79797 respectively blocks iLTP and restores tetanus induced LTP. Averaged EPSP are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. Upward arrows indicate the time of HFS.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Either thrombin or PAR1 blockade restore physiological tetanus induced LTP in OGD exposed hippocampal slices.(a) A brief exposure (3 minutes) to OGD induces iLTP and blocks stimulus onset LTP: a tetanic stimulation to the same pathway, adjusted to submaximal level (downward arrow), is able to produce a short-term but not a long-term potentiation. (b) Blockade of either thrombin or PAR1 through (b) 1 μM α-NAPAP or (c) 1 μM SCH79797 respectively blocks iLTP and restores tetanus induced LTP. Averaged EPSP are plotted versus time. Representative traces at indicated times (a, b) are shown for each section. Upward arrows indicate the time of HFS.
Mentions: Since iLTP is considered to be a pathological form of synaptic plasticity, which alters the plastic properties of healthy neuronal networks4, we reasoned that physiological, i.e., tetanus-induced LTP will be impaired in a network previously exposed to OGD. In order to test this hypothesis, in a two pathway experimental setting, hippocampal slices were once more exposed to OGD. This resulted in iLTP at both pathways recorded in parallel (Fig. 4a). When potentiation levels reached saturation, the stimulation intensity at one pathway was reduced to the level of baseline and a tetanic stimulation (100 Hz; 1 second) was then delivered at this pathway. Strikingly, the tetanus did not evoke LTP (0.993 ± 0.06 at 25 minutes after tetanic stimulation, n = 12, Fig. 4a) under these conditions.

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