Thrombin Induces Long-Term Potentiation of Reactivity to Afferent Stimulation and Facilitates Epileptic Seizures in Rat Hippocampal Slices: Toward Understanding the Functional Consequences of Cerebrovascular Insults

Abstract

The effects of thrombin, a blood coagulation serine protease, were studied in rat hippocampal slices, in an attempt to comprehend its devastating effects when released into the brain after stroke and head trauma. Thrombin acting through its receptor, protease-activated receptor 1 (PAR1), produced a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation, an effect that saturated the ability of the tissue to undergo tetanus-induced long-term potentiation. This effect was mediated by activation of a PAR1 receptor, because it was shared by a PAR1 agonist, and was blocked by its selective antagonist. An independent effect of thrombin involved the lowering of the threshold for generating epileptic seizures in CA3 region of the hippocampus. Thus, the experiments in a slice mimicked epileptic and cognitive dysfunction induced by thrombin in the brain, and suggest that these effects are mediated by activation of the PAR1 receptor.

Neuronal Protease-Activated Receptor 1 Drives Synaptic Retrograde Signaling Mediated by the Endocannabinoid 2-Arachidonoylglycerol

“…Previous studies with hippocampal slices demonstrated that PAR1 activation positively regulates neuronal excitatory synaptic activity (Gingrich et al, 2000;Lee et al, 2007;Maggio et al, 2008;Mannaioni et al, 2008). To the best of our knowledge, there are no studies reporting PAR1-induced suppression of excitatory transmission.…”

“…At cellular levels, PAR1 activation influences synaptic transmission. PAR1 activation potentiated NMDA receptor currents (Gingrich et al, 2000;Mannaioni et al, 2008), induced long-term potentiation (LTP) of excitatory transmission (Maggio et al, 2008) in CA1 pyramidal neurons of hippocampal slices, and enhanced spontaneous release of glutamate onto substantia gelatinosa neurons in spinal cord slices (Fujita et al, 2009). As to the mechanisms, several studies have demonstrated that PAR agonists activate astrocytic PAR1, rather than neuronal PAR1, and induce glutamate release from astrocytes, thereby activating neuronal NMDA receptors in hippocampal acute slices (Lee et al, 2007;Mannaioni et al, 2008;Shigetomi et al, 2008) and hippocampal coculture preparations (Lee et al, 2007).…”

Blood-Brain Barrier Permeability: From Bench to Bedside

“…It has been suggested that accumulated albumin binds to transforming growth factor beta receptor 2 (TGFbetaR2) in astrocytes and induces rapid astrocytic transformation and dysfunction David et al, 2009;Ivenset al, 2007;) In addition, leakage of some other serum-derived components into the extracellular space may also result in hyperexcitability and seizure onset. For example, it has been recently shown that the serum protein, thrombin, via receptors protease-activated receptor 1 (PAR1), produces a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation (Maggio et al, 2008). It should also be noted that in many cases of epilepsy, that BBB breakdown has been associated with early or delayed neuronal damage (Rigau et al, 2007;Tomkins et al, 2007;van Vliet et al, 2007).…”

Lack of association between the prothrombin rs1799963 polymorphism and juvenile myoclonic epilepsy

“…Thrombin, a serine protease essential in the coagulation cascade is involved in the production of seizures 6 . It was demonstrated that active thrombin injected into rat brains resulted in both electrographic and clinical seizures 7 .…”

“…It was demonstrated that active thrombin injected into rat brains resulted in both electrographic and clinical seizures 7 . It was proposed that thrombin, acting on its receptor, protease-activated receptor 1 (PAR1), has marked effects on the production of long-term potentiation (LTP) in responses to afferent stimulation and that it enhances the sensitivity to epileptic seizures in brain slices 6 . Thrombin may triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons 5,8,9 .…”