Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models.
Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models.
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增强 GABA 信号传导可改善 AD 小鼠模型中嗅球的异常伽马振荡
DOI：
10.1186/s13024-021-00434-7
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发表时间：
2021-03-04
影响因子：
15.1
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Chen M;Chen Y;Huo Q;Wang L;Tan S;Misrani A;Jiang J;Chen J;Chen S;Zhang J;Tabassum S;Wang J;Chen X;Long C;Yang L
在淀粉样蛋白β斑块沉积和学习记忆缺陷发作之前，阿尔茨海默病（AD）患者经历嗅觉功能障碍，其典型表现为检测、辨别和识别气味的能力降低。AD的啮齿类动物模型，如Tg2576和APP/PS1小鼠，也显示嗅觉受损，伴有嗅觉通路中异常的体内或体外γ节律。然而，电生理，生物化学和行为现象之间的机制关系仍然不清楚。为了解决AD模型中的上述问题，我们进行了局部场电位（LFP）的体内测量，结合体外嗅觉电图（EOG），全细胞贴片和场记录来评估嗅觉通路中的振荡和突触功能以及药理学调节，特别是在嗅球（OB）中。通过免疫印迹和荧光染色研究了OB的兴奋和抑制蛋白质水平，而行为研究评估了嗅觉和记忆功能。LFP测量表明，在3 - 5个月大的APP/PS1和3xTg小鼠中，即在斑块形成开始之前的年龄，OB中的γ振荡增加，伴随着嗅觉行为的改变。更少的嗅觉感觉神经元（OSNs）和减少EOG的M/T细胞的兴奋性反应的减少，表明M/T细胞的能力下降，触发中间神经元GABA释放的改变成对脉冲比（PPR），突触前参数。在突触后，GABAAR α 1和β 3亚基水平代偿性增加，随后出现更高幅度的抑制反应。引人注目的是，GABA摄取抑制剂噻加宾（TGB）改善异常γ振荡和GABAAR亚基的水平，这表明早期AD症状的潜在治疗策略。这些发现揭示了在AD发作之前作为核心指标的OB中增加的γ振荡，并揭示了OB中异常γ活性的潜在机制。这项研究表明，嗅觉行为和γ振荡的伴随功能障碍对AD的早期诊断有重要意义：特别是，对异常GABA能信号传导机制的认识可能有助于AD的诊断，并为AD的嗅觉损伤提供治疗策略。在线版本包含补充材料，可通过10.1186/s13024 - 021 - 00434 - 7获得。
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. The online version contains supplementary material available at 10.1186/s13024-021-00434-7.
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DOI：
10.3791/1850
发表时间：
2010-03-02
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Cygnar, Katherine D;Stephan, Aaron B;Zhao, Haiqing
通讯作者：
Zhao, Haiqing
DOI：
10.1111/ejn.13831
发表时间：
2018-10
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Butler JL;Hay YA;Paulsen O
通讯作者：
Paulsen O
影响因子：
5.3
作者：
Burton, Shawn D.;LaRocca, Greg;Urban, Nathaniel N.
通讯作者：
Urban, Nathaniel N.
DOI：
10.1056/nejmoa1706441
发表时间：
2018-05-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Egan MF;Kost J;Tariot PN;Aisen PS;Cummings JL;Vellas B;Sur C;Mukai Y;Voss T;Furtek C;Mahoney E;Harper Mozley L;Vandenberghe R;Mo Y;Michelson D
通讯作者：
Michelson D
影响因子：
7.7
作者：
Bolding, Kevin A.;Nagappan, Shivathmihai;Franks, Kevin M.
通讯作者：
Franks, Kevin M.