BACKGROUND Abnormal accumulation of amyloid β1-42 oligomers (AβO1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AβO1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AβO1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. RESULTS Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AβO1-42 causes synapse-specific dysfunction in PV and SST interneurons. AβO1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AβO1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AβO1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. CONCLUSIONS Our results reveal that AβO1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.

中文翻译：

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小白蛋白和生长抑素中间神经元的光遗传学激活选择性地恢复了β-淀粉样寡聚体削弱的θ嵌套γ振荡和振荡诱导的依赖于尖峰时间的长期增强作用。

背景技术淀粉样蛋白β1-42寡聚体（AβO1-42）的异常积累是阿尔茨海默氏病的标志，损害了海马θ嵌套的γ振荡和长期增强（LTP），这被认为是学习和记忆的基础。小白蛋白阳性（PV）和生长抑素阳性（SST）中间神经元与θ嵌套的γ示波和LTP诱导密切相关。但是，AβO1-42如何影响PV和SST中间神经元电路尚不清楚。通过对PV和SST中间神经元的光遗传学操纵和海马神经回路的计算模型，我们剖析了PV和SST中间神经元电路功能障碍对AβO1-42引起的海马theta嵌套伽马振荡和振荡诱导的LTP损伤的影响。结果在体内类似的，光遗传学上诱导的θ嵌套γ振荡期间，针对性的全细胞膜片钳记录和PV和SST中神经元的光遗传学操作揭示了AβO1-42引起PV和SST中神经元的突触特异性功能障碍。AβO1-42选择性破坏CA1锥体细胞（PC）到PV中间神经元和PV到PC的突触，从而损害theta嵌套的伽马振荡。相反，AβO1-42在不影响PC到SST或SST到PC的突触的同时，选择性地破坏了SST间神经元介导的对CA1 PC的抑制作用，从而削弱了由θ嵌套的伽马振荡诱导的依赖于尖峰时间的LTP（tLTP ）。分别通过PV和SST中间神经元的光遗传学活化，完全恢复了AβO1-42诱导的γ振荡和激光诱导的tLTP损伤。进一步支持PV和SST中神经元中突触特异的功能障碍。最后，包括CA1 PC，PV和SST中神经元在内的海马神经回路的计算模型证实了实验观察结果，并进一步揭示了PV和SST中神经元在θ嵌套伽马振荡和tLTP诱导中的独特功能。结论我们的结果表明，AβO1-42在PV和SST中间神经元中引起突触特异性功能障碍，这些中间神经元的光遗传学调节为恢复海马网络振荡和阿尔茨海默氏病的突触可塑性损伤提供了潜在的治疗靶点。SST中间神经元和SST中间神经元证实了实验观察，并进一步揭示了PV和SST中间神经元在θ嵌套伽马振荡和tLTP诱导中的独特功能。结论我们的结果表明，AβO1-42在PV和SST中间神经元中引起突触特异性功能障碍，这些中间神经元的光遗传学调节为恢复海马网络振荡和阿尔茨海默氏病的突触可塑性损伤提供了潜在的治疗靶点。SST中间神经元和SST中间神经元证实了实验观察，并进一步揭示了PV和SST中间神经元在θ嵌套伽马振荡和tLTP诱导中的独特功能。结论我们的结果表明，AβO1-42在PV和SST中间神经元中引起突触特异性功能障碍，这些中间神经元的光遗传学调节为恢复海马网络振荡和阿尔茨海默氏病的突触可塑性损伤提供了潜在的治疗靶点。