title: Thrombin regulation of synaptic transmission: implications for seizure onset.
abstract: Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of thrombin and a PAR-1 agonist on neuronal excitability and synaptic currents was assessed by whole cell-patch recordings of pyramidal neurons in rat hippocampal slices. In addition, PAR-1 distribution in different hippocampal regions was assessed using immunohistochemistry. We found that thrombin caused an increase in spontaneous action potential discharges of CA3 but not of CA1 pyramidal neurons. When excitatory synaptic activity was blocked, thrombin caused a marked reduction in spontaneous IPSCs in CA3 neurons and a marked increase in the frequency of IPSCs in CA1 neurons. These effects are likely to be local, as they were reproduced in TTX-treated slices. In parallel, thrombin increased both the frequency and the amplitude of mEPSCs only in CA3 neurons. These effects were blocked by a selective PAR-1 antagonist. The higher expression of PAR-1 in stratum lucidum of CA3 is correlated with the effects of thrombin in this region. These results suggest that thrombin triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons, providing a novel insight to the pathophysiology of seizures following cerebrovascular events and present new avenues for therapeutic intervention.
authors.affiliation: Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, 52621 Tel HaShomer, Israel. nicola.maggio@sheba.health.gov.il
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.forename: Carlo
authors.initials: C
authors.lastname: Cavaliere
authors.forename: Michele
authors.initials: M
authors.lastname: Papa
authors.forename: Ilan
authors.initials: I
authors.lastname: Blatt
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.forename: Menahem
authors.initials: M
authors.lastname: Segal
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism*
chemical_list: D044463:Receptor, PAR-1; D013917:Thrombin