Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity.
Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity.
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DOI：
10.1016/j.bbi.2015.08.023
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Stranahan AM
中科院分区：
文献类型：
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作者：
Hao S;Dey A;Yu X;Stranahan AM
肥胖增加了与年龄相关的认知能力下降的风险，并伴有外周炎症。啮齿类动物肥胖模型的研究表明，海马功能受损与小胶质细胞激活有关，但神经元/小胶质细胞相互作用可能在肥胖中受到干扰的可能性从未被直接检验过。本研究的目的是确定高脂肪饮食引起的肥胖是否会促进小胶质细胞的突触剥离，以及是否有任何潜在的变化可以通过恢复低脂肪饮食（LFD）来逆转。时间过程实验显示，在HFD治疗3个月后，海马炎症细胞因子诱导和突触蛋白表达的丧失都可以检测到，因此，后续各组小鼠在HFD治疗3个月后，再切换到LFD治疗2个月（HFD/LFD）。在此期间，额外的HFD小鼠继续接受HFD (HFD/HFD)，而另一组小鼠在整个实验期间维持LFD （LFD/LFD）。饮食性肥胖损害了海马依赖记忆，降低了长期增强（LTP），并诱导了海马小胶质细胞中激活标志物主要组织相容性复合体II （MHCII）的表达。饮食逆转仅部分减弱了HFD/LFD小鼠的肥胖增加，但可塑性缺陷和MHCII诱导归一化到LFD/LFD小鼠的范围内。小胶质细胞的激活和海马功能的缺陷伴随着小胶质细胞过程和突触点之间的空间关系的扰动。对HFD/HFD小鼠分离的初级小胶质细胞的分析显示，用ph敏感荧光团标记的突触体的内化选择性增加。综上所述，这些发现表明，饮食性肥胖可可逆地损害海马功能，而这种缺陷可能归因于小胶质细胞的突触剥离。
Obesity increases risk of age-related cognitive decline and is accompanied by peripheral inflammation. Studies in rodent models of obesity have demonstrated that impaired hippocampal function correlates with microglial activation, but the possibility that neuron/microglia interactions might be perturbed in obesity has never been directly examined. The goal of this study was to determine whether high fat diet-induced obesity promotes synaptic stripping by microglia, and whether any potential changes might be reversible by a return to low-fat diet (LFD). Time course experiments revealed that hippocampal inflammatory cytokine induction and loss of synaptic protein expression were detectable after three months of HFD, therefore subsequent groups of mice were maintained on HFD for three months before being switched to LFD for an additional two months on LFD (HFD/LFD). Additional HFD mice continued to receive HFD during this period (HFD/HFD), while another group of mice were maintained on LFD throughout the experiment (LFD/LFD). Dietary obesity impaired hippocampus-dependent memory, reduced long-term potentiation (LTP), and induced expression of the activation marker major histocompatibility complex II (MHCII) in hippocampal microglia. Diet reversal only partially attenuated increases in adiposity in HFD/LFD mice, but plasticity deficits and MHCII induction were normalized to within the range of LFD/LFD mice. Microglial activation and deficits in hippocampal function were accompanied by perturbation of spatial relationships between microglial processes and synaptic puncta. Analysis of primary microglia isolated from HFD/HFD mice revealed selective increases in internalization of synaptosomes labeled with a pH-sensitive fluorophore. Taken together, these findings indicate that dietary obesity reversibly impairs hippocampal function, and that deficits may be attributable to synaptic stripping by microglia.