Impairment of Dendrodendritic Inhibition in the Olfactory Bulb of APP/PS1 Mice
Impairment of Dendrodendritic Inhibition in the Olfactory Bulb of APP/PS1 Mice
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APP/PS1 小鼠嗅球中树突状体抑制的损害
DOI：
10.3389/fnagi.2019.00002
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发表时间：
2019-01-24
影响因子：
4.8
通讯作者：
Ling, Shucai
中科院分区：
文献类型：
--
作者：
Li, Weiyun;Li, Shanshan;Ling, Shucai
嗅觉功能障碍是阿尔茨海默病（AD）的早期事件。然而，AD相关的嗅球（OB）变化的机制仍然未知。OB中的颗粒细胞（GC）通过相互的树-树突触调节二尖瓣细胞（MC）的活动，这对于嗅觉信号处理和气味辨别至关重要。然而，树突突触的形态和功能的变化之间的关系，特别是局部场电位（LFPs）作为AD患者的嗅觉障碍的后果还没有被调查。在这里，我们研究了老化过程中淀粉样前体蛋白（APP）/PS1小鼠和年龄匹配的对照小鼠OB中的GC对MC的树突状抑制诱导的形态和功能变化，特别是，我们专注于嗅觉障碍的影响在树突状突触结构和LFPs。我们发现，嗅觉障碍与APP/PS1小鼠OB中淀粉样蛋白β（A β）沉积增加有关，这些小鼠还表现出GC和MC形态的异常变化，GC树突棘密度降低，GC和MC之间的树突-树突突触界面受损。此外，在APP/PS1小鼠OB的MC的γ振荡和放电率的异常增强记录的多电极阵列（MEA）。局部应用GABA（A）R激动剂几乎消除了AD晚期外丛状层（EPL）γ振荡的异常增加，而GABA（A）R拮抗剂则加重了g振荡。根据我们的研究结果，我们得出结论，改变形态的GC的突触结构，功能障碍的相互之间的MC和GC的树-树突触，和异常g振荡的EPL可能有助于嗅觉功能障碍在AD。
Olfactory dysfunction is an early event in Alzheimer's disease (AD). However, the mechanism underlying the AD-related changes in the olfactory bulb (OB) remains unknown. Granule cells (GCs) in the OB regulate the activity of mitral cells (MCs) through reciprocal dendrodendritic synapses, which is crucial for olfactory signal processing and odor discrimination. Nevertheless, the relationships between the morphological and functional changes of dendrodendritic synapses, particularly the local field potentials (LFPs) as a consequence of olfactory disorders in patients with AD have not been investigated. Here, we studied the morphological and functional changes induced by dendrodendritic inhibition in GCs onto MCs in the OB of amyloid precursor protein (APP)/PS1 mice and age-matched control mice during aging, particular, we focused on the effects of olfactory disorder in the dendrodendritic synaptic structures and the LFPs. We found that olfactory disorder was associated with increased amyloid-beta (A beta) deposits in the OB of APP/PS1 mice, and those mice also exhibited abnormal changes in the morphology of GCs and MCs, a decreased density of GC dendritic spines and impairments in the synaptic interface of dendrodendritic synapses between GCs and MCs. In addition, the aberrant enhancements in the gamma oscillations and firing rates of MCs in the OB of APP/PS1 mice were recorded by multi-electrode arrays (MEAs). The local application of a GABA(A)R agonist nearly abolished the aberrant increase in gamma oscillations in the external plexiform layer (EPL) at advanced stages of AD, whereas a GABA(A)R antagonist aggravated the g oscillations. Based on our findings, we concluded that the altered morphologies of the synaptic structures of GCs, the dysfunction of reciprocal dendrodendritic synapses between MCs and GCs, and the abnormal g oscillations in the EPL might contribute to olfactory dysfunction in AD.