Post-tetanic potentiation lowers the energy barrier for synaptic vesicle fusion independently of Synaptotagmin-1.

Previously, we showed that modulation of the energy barrier for synaptic vesicle fusion boosts release rates supralinearly (Schotten, 2015). Here we show that mouse hippocampal synapses employ this principle to trigger Ca2+-dependent vesicle release and post-tetanic potentiation (PTP). We assess energy barrier changes by fitting release kinetics in response to hypertonic sucrose. Mimicking activation of the C2A domain of the Ca2+-sensor Synaptotagmin-1 (Syt1), by adding a positive charge (Syt1D232N) or increasing its hydrophobicity (Syt14W), lowers the energy barrier. Removing Syt1 or impairing its release inhibitory function (Syt19Pro) increases spontaneous release without affecting the fusion barrier. Both phorbol esters and tetanic stimulation potentiate synaptic strength, and lower the energy barrier equally well in the presence and absence of Syt1. We propose a model where tetanic stimulation activates Syt1-independent mechanisms that lower the energy barrier and act additively with Syt1-dependent mechanisms to produce PTP by exerting multiplicative effects on release rates.

Ventilation according to the open lung concept attenuates pulmonary inflammatory response in cardiac surgery.

OBJECTIVE: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response, which is correlated with outcome. We hypothesized that ventilation according to the open lung concept (OLC) attenuates cytokine release. METHODS: A prospective, single center randomized controlled clinical study containing 62 patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Before surgery, patients were randomly assigned to three groups: (1) conventional mechanical ventilation (CV), (2) OLC started after arrival on the ICU (late open lung, LOL), and (3) OLC started directly after intubation (early open lung, EOL). In both OLC groups, recruitment maneuvers were applied until PaO(2)/FiO(2)>50. The CV group received no recruitment maneuvers. Interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured preoperatively, immediately after cessation of CPB, and 3h, 5h, 24h, 2, and 3 days after cessation of CPB. RESULTS: CPB caused a significant increase of IL-6, IL-8, and IL-10 in all groups. Thereafter, IL-8 decreased significantly more rapidly in both OLC groups compared to CV. IL-10 decreased significantly more rapidly after CPB only in the EOL group, compared with CV. Three hours after cessation of the CPB, IL-10 was already comparable with preoperative levels in the EOL group, but not in the LOL or CV group. IL-6, TNF-alpha, and IFN-gamma did not differ significantly between groups. CONCLUSIONS: OLC ventilation leads to an attenuated inflammatory response, presumably by reducing additional lung injury after cardiac surgery. Studies on cytokines after cardiac surgery should take these findings into account.