Amyloid β causes excitation/inhibition imbalance through dopamine receptor 1-dependent disruption of fast-spiking GABAergic input in anterior cingulate cortex.
Amyloid β causes excitation/inhibition imbalance through dopamine receptor 1-dependent disruption of fast-spiking GABAergic input in anterior cingulate cortex.
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淀粉样蛋白 β 通过多巴胺受体 1 依赖性破坏前扣带皮层中快速尖峰 GABA 能输入，导致兴奋/抑制失衡
DOI：
10.1038/s41598-017-18729-5
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发表时间：
2018-01-10
影响因子：
4.6
通讯作者：
Cheng Z
中科院分区：
文献类型：
--
作者：
Ren SQ;Yao W;Yan JZ;Jin C;Yin JJ;Yuan J;Yu S;Cheng Z
阿尔茨海默病(AD)是导致老年人痴呆的最常见原因。在AD发病的早期，可溶性淀粉样蛋白(β-A-loid，A-β)诱导突触功能障碍，扰乱神经回路的兴奋/抑制平衡，进而改变正常的神经网络活动，导致认知功能下降，但其潜在机制尚不清楚。在此，我们利用小鼠急性脑片的全细胞记录，发现50 nM Aβ通过抑制抑制性突触传递，在AD最脆弱的区域之一的扣带皮质诱导兴奋性锥体细胞的过度兴奋。此外，通过同时记录多个细胞，我们发现来自快峰(FS)中间神经元而不是非FS中间神经元的锥体细胞的抑制性神经支配被Aβ显著干扰，而突触前抑制性神经递质γ-氨基丁酸的释放的扰动是这种抑制性输入干扰的基础。最后，我们确认多巴胺对FS中间神经元多巴胺D_1受体的作用增加是导致A-β引起GABA能传入扰动和兴奋/抑制失衡的关键病理因素。因此，我们得出结论，依赖多巴胺受体1的FS GABA能抑制输入的干扰在β诱导的前扣带回兴奋/抑制失衡中起关键作用。
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. At the early stages of AD development, the soluble β-amyloid (Aβ) induces synaptic dysfunction, perturbs the excitation/inhibition balance of neural circuitries, and in turn alters the normal neural network activity leading to cognitive decline, but the underlying mechanisms are not well established. Here by using whole-cell recordings in acute mouse brain slices, we found that 50 nM Aβ induces hyperexcitability of excitatory pyramidal cells in the cingulate cortex, one of the most vulnerable areas in AD, via depressing inhibitory synaptic transmission. Furthermore, by simultaneously recording multiple cells, we discovered that the inhibitory innervation of pyramidal cells from fast-spiking (FS) interneurons instead of non-FS interneurons is dramatically disrupted by Aβ, and perturbation of the presynaptic inhibitory neurotransmitter gamma-aminobutyric acid (GABA) release underlies this inhibitory input disruption. Finally, we identified the increased dopamine action on dopamine D1 receptor of FS interneurons as a key pathological factor that contributes to GABAergic input perturbation and excitation/inhibition imbalance caused by Aβ. Thus, we conclude that the dopamine receptor 1-dependent disruption of FS GABAergic inhibitory input plays a critical role in Aβ-induced excitation/inhibition imbalance in anterior cingulate cortex.
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影响因子：
2.6
作者：
Cellot G;Cherubini E
通讯作者：
Cherubini E
DOI：
10.1073/pnas.1206171109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Busche, Marc Aurel;Chen, Xiaowei;Konnerth, Arthur
通讯作者：
Konnerth, Arthur
影响因子：
5.3
作者：
Liu, Qiang;Xie, Xitao;Wu, Jie
通讯作者：
Wu, Jie
影响因子：
4.8
作者：
Martorana A;Koch G
通讯作者：
Koch G
影响因子：
3.3
作者：
Born, H. A.
通讯作者：
Born, H. A.