Optical assays of synaptic strength could facilitate studies of neuronal transmission and its dysregulation in disease. Here we introduce a genetic toolbox for all-optical interrogation of synaptic electrophysiology (synOptopatch) via mutually exclusive expression of a channelrhodopsin actuator and an archaerhodopsin-derived voltage indicator. Optically induced activity in the channelrhodopsin-expressing neurons generated excitatory and inhibitory postsynaptic potentials that we optically resolved in reporter-expressing neurons. We further developed a yellow spine-targeted Ca²⁺ indicator to localize optogenetically triggered synaptic inputs. We demonstrated synOptopatch recordings in cultured rodent neurons and in acute rodent brain slice. In synOptopatch measurements of primary rodent cultures, acute ketamine administration suppressed disynaptic inhibitory feedbacks, mimicking the effect of this drug on network function in both rodents and humans. We localized this action of ketamine to excitatory synapses onto interneurons. These results establish an in vitro all-optical model of disynaptic disinhibition, a synaptic defect hypothesized in schizophrenia-associated psychosis.

突触强度的光学测定可以促进神经元传递及其在疾病中的失调的研究。在这里，我们介绍了一个遗传工具箱，用于通过通道视紫红质致动器和古视紫红质衍生电压指示器的互斥表达来对突触电生理学 (synOptopatch) 进行全光学询问。表达通道视紫红质的神经元中的光诱导活动产生兴奋性和抑制性突触后电位，我们在表达报告子的神经元中光学解决了这些电位。我们进一步开发了黄色脊柱靶向 Ca ²⁺用于定位光遗传学触发的突触输入的指标。我们在培养的啮齿动物神经元和急性啮齿动物脑切片中展示了 synOptopatch 记录。在对初级啮齿动物培养物的 synOptopatch 测量中，急性氯胺酮给药抑制了非突触抑制反馈，模拟了这种药物对啮齿动物和人类网络功能的影响。我们将氯胺酮的这种作用定位于中间神经元上的兴奋性突触。这些结果建立了一个体外全光学模型的突触去抑制，这是一种在精神分裂症相关精神病中假设的突触缺陷。