Olfactory damage develops at the early stages of Alzheimer's disease (AD). While amyloid-β (Aβ) oligomers are shown to impair inhibitory circuits in the olfactory bulb (OB), its underlying mechanisms remain unclear. Here, we investigated the olfactory dysfunction due to impaired inhibitory transmission to mitral cells (MCs) of the OB in APP/PS1 mice. Using electrophysiological studies, we found that MCs exhibited increased spontaneous firing rates as early as 3 months, much before development of Aβ deposits in the brain. Furthermore, the frequencies but not amplitudes of MC inhibitory postsynaptic currents decreased markedly, suggesting that presynaptic GABA release is impaired while postsynaptic GABA_A receptor responses remain intact. Notably, muscimol, a GABA_A receptor agonist, improved odor identification and discrimination behaviors in APP/PS1 mice, reduced MC basal firing activity, and rescued inhibitory circuits along with reducing the Aβ burden in the OB. Our study links the presynaptic deficits of GABAergic transmission to olfactory dysfunction and subsequent AD development and implicates the therapeutic potential of maintaining local inhibitory microcircuits against early AD progression.

嗅觉损伤发生在阿尔茨海默病 (AD) 的早期阶段。虽然显示淀粉样蛋白-β (Aβ) 寡聚体会损害嗅球 (OB) 中的抑制回路，但其潜在机制仍不清楚。在这里，我们研究了由于 APP/PS1 小鼠 OB 对二尖瓣细胞 (MCs) 的抑制性传递受损而导致的嗅觉功能障碍。使用电生理学研究，我们发现 MC 早在 3 个月时就表现出增加的自发放电率，远远早于大脑中 Aβ 沉积物的发展。此外，MC 抑制性突触后电流的频率而非幅度显着降低，表明突触前 GABA 释放受损，而突触后 GABA _A受体反应保持完整。值得注意的是，蝇蕈醇，一种 GABA _A受体激动剂，改善了 APP/PS1 小鼠的气味识别和辨别行为，降低了 MC 基础放电活动，并在减少 OB 中的 Aβ 负担的同时挽救了抑制回路。我们的研究将 GABA 能传递的突触前缺陷与嗅觉功能障碍和随后的 AD 发展联系起来，并暗示维持局部抑制性微电路对早期 AD 进展的治疗潜力。