General anesthetics disrupt brain network dynamics through multiple pathways, in part through postsynaptic potentiation of inhibitory ion channels as well as presynaptic inhibition of neuroexocytosis. Common clinical general anesthetic drugs, such as propofol and isoflurane, have been shown to interact and interfere with core components of the exocytic release machinery to cause impaired neurotransmitter release. Recent studies however suggest that these drugs do not affect all synapse subtypes equally. We investigated the role of the presynaptic release machinery in multiple neurotransmitter systems under isoflurane general anesthesia in the adult female Drosophila brain using live-cell super–resolution microscopy and optogenetic readouts of exocytosis and neural excitability. We activated neurotransmitter-specific mushroom body output neurons and imaged presynaptic function under isoflurane anesthesia. We found that isoflurane impaired synaptic release and presynaptic protein dynamics in excitatory cholinergic synapses. In contrast, isoflurane had little to no effect on inhibitory GABAergic or glutamatergic synapses. These results present a distinct inhibitory mechanism for general anesthesia, whereby neuroexocytosis is selectively impaired at excitatory synapses, while inhibitory synapses remain functional. This suggests a presynaptic inhibitory mechanism that complements the other inhibitory effects of these drugs.

全身麻醉药通过多种途径破坏大脑网络动态，部分是通过抑制性离子通道的突触后增强以及神经胞吐作用的突触前抑制。常见的临床全身麻醉药物，如丙泊酚和异氟烷，已被证明会与胞吐释放机制的核心成分相互作用并干扰，导致神经递质释放受损。然而，最近的研究表明这些药物对所有突触亚型的影响并不相同。我们使用活细胞超分辨率显微镜和胞吐作用和神经兴奋性的光遗传学读数，研究了异氟烷全身麻醉下成年雌性果蝇大脑中突触前释放机制在多个神经递质系统中的作用。我们激活了神经递质特异性蘑菇体输出神经元，并在异氟烷麻醉下对突触前功能进行了成像。我们发现异氟醚会损害兴奋性胆碱能突触中的突触释放和突触前蛋白质动力学。相比之下，异氟醚对抑制性 GABA 能或谷氨酸能突触几乎没有影响。这些结果提出了全身麻醉的独特抑制机制，其中神经胞吐作用在兴奋性突触处选择性受损，而抑制性突触保持功能。这表明突触前抑制机制可以补充这些药物的其他抑制作用。