Short-term synaptic facilitation occurs during high-frequency stimulation, is known to be dependent on presynaptic calcium ions, and persists for tens of milliseconds after a presynaptic action potential. We have used the frog neuromuscular junction as a model synapse for both experimental and computer simulation studies aimed at testing various mechanistic hypotheses proposed to underlie short-term synaptic facilitation. Building off our recently reported excess-calcium-binding-site model of synaptic vesicle release at the frog neuromuscular junction (Dittrich M, Pattillo JM, King JD, Cho S, Stiles JR, Meriney SD. Biophys J 104: 2751–2763, 2013), we have investigated several mechanisms of short-term facilitation at the frog neuromuscular junction. Our studies place constraints on previously proposed facilitation mechanisms and conclude that the presence of a second class of calcium sensor proteins distinct from synaptotagmin can explain known properties of facilitation observed at the frog neuromuscular junction. We were further able to identify a novel facilitation mechanism, which relied on the persistent binding of calcium-bound synaptotagmin molecules to lipids of the presynaptic membrane. In a real physiological context, both mechanisms identified in our study (and perhaps others) may act simultaneously to cause the experimentally observed facilitation. In summary, using a combination of computer simulations and physiological recordings, we have developed a stochastic computer model of synaptic transmission at the frog neuromuscular junction, which sheds light on the facilitation mechanisms in this model synapse.

Background Prolonged periods of family caregiving can induce stress levels that may negatively influence caregiver health. However, the physiologic effect of psychological distress in oncology family caregivers has received little attention. Therefore we aimed to determine longitudinal profiles of inflammatory cytokines (IL-6 and IL-1ra) in neuro-oncology caregivers and identify associations between psychological distress and cytokine levels. Methods Depressive symptoms, anxiety, caregiver burden and blood were collected from 108 adult caregivers at adult patients' diagnosis, 4-, 8-, and 12-months. Trajectory analyses of log transformed cytokine levels were performed. Multiple logistic regression analyses evaluated the impact of psychological distress on cytokine levels. Results For both cytokines, two distinct populations were identified, neither of which changed over time. High IL-1ra was associated with male caregivers with anxiety (OR=1.7; 95%CI 1.06-2.83) and obese caregivers (BMI=40) who felt burdened due to disrupted schedules (OR=1.3; 95%CI 1.02-1.77). Conversely, caregivers with a healthy weight (BMI=25) who felt burdened due to disrupted schedules were less likely to have high IL-1ra (OR=0.71; 95%CI 0.54-0.92). Caregivers ≤30 years old with lower self-esteem from caregiving were 1.16 times (95%CI 1.04-1.30) more likely to have high IL-6. Conclusions Analysis demonstrated groups of family caregivers with high and low levels of systemic inflammation and these levels did not change longitudinally over the care trajectory. Poor physical health in family caregivers may have a negative impact on the burden placed on the healthcare system in general and on the well-being of neuro-oncology patients in particular.

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Las investigaciones de terreno sobre las cuales se basa en parte este artículo, fueron auspiciadas por la Grace y Henry Doherty Foundation de Nueva York, y últimamente por el Instituto Colombiano de Antropología.