Abstract：
Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer\'s disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aβ and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aβ, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aβ: β-amyloid, GABA: gamma-aminobutyric acid.
摘要：
嗅觉功能障碍越来越被认为是阿尔茨海默病(AD)的早期指标。在AD的初始阶段，GABA能功能的畸变和嗅球（OB）内的兴奋性/抑制性（E/I）平衡与嗅觉障碍有关。虽然神经调节素1（NRG1）/ErbB4信号通路已知可调节大脑中的GABA能传递，并与各种神经精神疾病有关，其在早期AD相关嗅觉损害中的具体作用尚不完全清楚.这项研究表明，嗅觉功能障碍先于年轻成年APP/PS1小鼠的认知能力下降，其特征是OB中NRG1和ErbB4的水平降低。进一步的研究表明，小白蛋白中间神经元中ErbB4的缺失减少了GABA能的传递，并增加了OB中二尖瓣和簇绒细胞（M/Ts）的过度兴奋性，从而加速年轻成年APP/PS1小鼠的嗅觉功能障碍。此外,ErbB4缺乏与Aβ和BACE1介导的APP裂解的积累增加有关，随着OB中CDK5信号增强。发现NRG1输注到OB中可增强M/Ts中的GABA能传递并减轻年轻成年APP/PS1小鼠的嗅觉功能障碍。这些发现强调了NRG1/ErbB4信号在调节OB内GABA能传递和E/I平衡中的关键作用，导致年轻成年APP/PS1小鼠的嗅觉障碍，并为AD的早期干预策略提供新的见解。这项工作表明，ErbB4缺乏增加了Aβ的负担，GABA能传递受损，并破坏了OB中二尖瓣和簇绒细胞（M/Ts）的E/I平衡，最终导致年轻成年APP/PS1小鼠的嗅觉功能障碍。NRG1可以增强GABA能传递，拯救M/Ts中的E/I失衡，并减轻年轻成年APP/PS1小鼠的嗅觉功能障碍。OB：嗅球，E/I：激发/抑制，Pr：释放的概率，PV：小白蛋白中间神经元，Aβ：β-淀粉样蛋白，GABA:γ-氨基丁酸。
