Queensland Brain Institute, The University of Queensland, Brisbane 4072, Queensland, Australia.
School of Medical Sciences, The University of New South Wales, Sydney 2052, New South Wales, Australia.
eNeuro. 2020 Feb 28;7(1). doi: 10.1523/ENEURO.0422-19.2020. Print 2020 Jan/Feb.
Propofol is the most common general anesthetic used for surgery in humans, yet its complete mechanism of action remains elusive. In addition to potentiating inhibitory synapses in the brain, propofol also impairs excitatory neurotransmission. We use electrophysiological recordings from individual glutamatergic boutons in male and female larval motor nerve terminals to characterize this effect. We recorded from two bouton types, which have distinct presynaptic physiology and different average numbers of release sites or active zones. We show that a clinically relevant dose of propofol (3 μm) impairs neurotransmitter release similarly at both bouton types by decreasing the number of active release sites by half, without affecting release probability. In contrast, an analog of propofol has no effect on glutamate release. Coexpressing a truncated syntaxin1A protein in presynaptic boutons completely blocked this effect of propofol. Overexpressing wild-type syntaxin1A in boutons also conferred a level of resistance by increasing the number of active release sites to a physiological ceiling set by the number of active zones or T-bars, and in this way counteracting the effect of propofol. These results point to the presynaptic release machinery as a target for the general anesthetic. Proportionally equivalent effects of propofol on the number of active release sites across the different bouton types suggests that glutamatergic circuits that involve smaller boutons with fewer release sites may be more vulnerable to the presynaptic effects of the drug.
丙泊酚是人类手术中最常用的全身麻醉剂，但它的作用机制仍不清楚。除了增强大脑中的抑制性突触外，丙泊酚还会损害兴奋性神经传递。我们使用雄性和雌性幼虫运动神经末梢单个谷氨酸能末梢的电生理记录来描述这种效应。我们记录了两种类型的末梢，它们具有不同的突触前生理学和不同的平均释放位点或活性区数量。我们表明，临床相关剂量的丙泊酚（3μm）通过将活性释放位点的数量减少一半，而不影响释放概率，对两种末梢类型的神经递质释放都有类似的损害作用。相比之下，丙泊酚的类似物对谷氨酸释放没有影响。在突触前末梢中共同表达截断的 syntaxin1A 蛋白完全阻断了丙泊酚的这种作用。在末梢中过表达野生型 syntaxin1A 也通过增加活性释放位点的数量来达到由活性区或 T 型条数量设定的生理上限，从而抵抗丙泊酚的作用，从而赋予对这种作用的抵抗力。这些结果表明，突触前释放机制是全身麻醉剂的作用靶点。丙泊酚对不同末梢类型的活性释放位点数量的比例等效作用表明，涉及释放位点较少的较小末梢的谷氨酸能回路可能更容易受到药物的突触前作用的影响。
