Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

中文翻译：

---

增强 GABA 能信号改善 AD 小鼠模型中嗅球的异常伽马振荡

在淀粉样蛋白-β 斑块沉积和学习记忆障碍开始之前，阿尔茨海默病 (AD) 患者会出现嗅觉功能障碍，其典型特征是检测、辨别和识别气味的能力下降。AD 的啮齿动物模型，例如 Tg2576 和 APP/PS1 小鼠，也表现出嗅觉受损，伴随着体内或体外嗅觉通路中的异常伽马节律。然而，电生理、生化和行为现象之间的机械关系仍不清楚。为了解决 AD 模型中的上述问题，我们结合体外嗅觉图 (EOG)、全细胞贴片和场记录，对局部场电位 (LFP) 进行了体内测量，以评估振荡和突触功能以及药理调节在嗅觉通路中，特别是在嗅球（OB）中。通过蛋白质印迹和荧光染色研究了参与 OB 激发和抑制的蛋白质水平，而行为研究则评估了嗅觉和记忆功能。LFP 测量表明 OB 中伽马振荡的增加伴随着 APP/PS1 和 3xTg 小鼠在 3-5 个月大时嗅觉行为的改变，即斑块形成开始之前的年龄。更少的嗅觉感觉神经元 (OSN) 和降低的 EOG 导致 M/T 细胞兴奋性反应的降低，表明 M/T 细胞触发中间神经元 GABA 释放的能力降低，由改变的配对脉冲比 (PPR) 表明，突触前参数。突触后，GABAAR α1 和 β3 亚基的水平补偿性增加，随后抑制反应的幅度更大。引人注目的是，GABA 摄取抑制剂 tiagabine (TGB) 改善了异常的伽马振荡和 GABAAR 亚基的水平，表明了早期 AD 症状的潜在治疗策略。这些发现揭示了 OB 中增加的伽马振荡作为 AD 发作之前的核心指标，并揭示了 OB 中异常伽马活动的潜在机制。这项研究表明，嗅觉行为和伽马振荡的伴随功能障碍对早期 AD 诊断具有重要意义：特别是，对异常 GABA 信号机制的认识可能有助于诊断并提出 AD 嗅觉损伤的治疗策略。GABA 摄取抑制剂 tiagabine (TGB) 改善了异常的伽马振荡和 GABAAR 亚基的水平，表明了早期 AD 症状的潜在治疗策略。这些发现揭示了 OB 中增加的伽马振荡作为 AD 发作之前的核心指标，并揭示了 OB 中异常伽马活动的潜在机制。这项研究表明，嗅觉行为和伽马振荡的伴随功能障碍对早期 AD 诊断具有重要意义：特别是，对异常 GABA 信号机制的认识可能有助于诊断并提出 AD 嗅觉损伤的治疗策略。GABA 摄取抑制剂 tiagabine (TGB) 改善了异常的伽马振荡和 GABAAR 亚基的水平，表明了早期 AD 症状的潜在治疗策略。这些发现揭示了 OB 中增加的伽马振荡作为 AD 发作之前的核心指标，并揭示了 OB 中异常伽马活动的潜在机制。这项研究表明，嗅觉行为和伽马振荡的伴随功能障碍对早期 AD 诊断具有重要意义：特别是，对异常 GABA 信号机制的认识可能有助于诊断并提出 AD 嗅觉损伤的治疗策略。这些发现揭示了 OB 中增加的伽马振荡作为 AD 发作之前的核心指标，并揭示了 OB 中异常伽马活动的潜在机制。这项研究表明，嗅觉行为和伽马振荡的伴随功能障碍对早期 AD 诊断具有重要意义：特别是，对异常 GABA 信号机制的认识可能有助于诊断并提出 AD 嗅觉损伤的治疗策略。这些发现揭示了 OB 中增加的伽马振荡作为 AD 发作之前的核心指标，并揭示了 OB 中异常伽马活动的潜在机制。这项研究表明，嗅觉行为和伽马振荡的伴随功能障碍对早期 AD 诊断具有重要意义：特别是，对异常 GABA 信号机制的认识可能有助于诊断并提出 AD 嗅觉损伤的治疗策略。