Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex.
Vagal nerve stimulation modifies neuronal activity and the proteome of excitatory synapses of amygdala/piriform cortex.
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DOI：
10.1111/jnc.13931
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发表时间：
2017-03
影响因子：
4.7
通讯作者：
McNamara JO
中科院分区：
文献类型：
--
作者：
Alexander GM;Huang YZ;Soderblom EJ;He XP;Moseley MA;McNamara JO
迷走神经刺激（VNS）疗法是美国食品和药物管理局批准的神经治疗药物，用于医学难治性部分性癫痫和难治性抑郁症。其有益作用的分子机制尚不清楚。我们假设一种机制涉及中枢神经系统兴奋性突触的神经元活动依赖性修饰。为了开始验证这一假设，我们询问VNS是否改变了杏仁核和海马神经元的活动。从成年，自由活动的大鼠的神经元记录显示，在杏仁核和海马的活动被修改后，立即通过VNS的应用程序，并检测到1周的刺激后的变化。为了研究VNS是否改变兴奋性突触的蛋白质组，我们建立了一个无标记，定量液相色谱-串联质谱工作流程，使全球分析的突触后密度（PSD）蛋白质组的成分。PSD蛋白从杏仁核/梨状皮质的VNS或假人治疗的大鼠1周的刺激后，生化纯化，并通过液相色谱-串联质谱分析定量个别PSD蛋白水平。我们确定了1899个独特的肽，对应于PSD组分中的425种蛋白质，其中22种蛋白质的表达水平受到VNS的差异调节，变化大于150%。PSD样本的蛋白质印迹分析证实了这些蛋白质的一个子集的变化，包括抗癫痫药物加巴喷丁的主要靶点neurexin-1α、钙粘蛋白13和电压依赖性钙通道α2δ1的表达显著增加，以及电压依赖性钙通道γ3的表达减少。这些结果表明，迷走神经刺激通过调节PSD蛋白质组的一个子集来调节兴奋性突触。我们的研究揭示了VNS的分子靶点，并指出其有益作用的可能机制，包括兴奋性突触的活动依赖性形成。
Vagal Nerve Stimulation (VNS) Therapy® is a United States Food and Drug Administration approved neurotherapeutic for medically refractory partial epilepsy and treatment-resistant depression. The molecular mechanisms underlying its beneficial effects are unclear. We hypothesized that one mechanism involves neuronal activity-dependent modifications of central nervous system excitatory synapses. To begin to test this hypothesis, we asked whether VNS modifies the activity of neurons in amygdala and hippocampus. Neuronal recordings from adult, freely moving rats revealed that activity in both amygdala and hippocampus was modified by VNS immediately after its application, and changes were detected following 1 week of stimulation. To investigate whether VNS modifies the proteome of excitatory synapses, we established a label-free, quantitative liquid chromatography-tandem mass spectrometry workflow that enables global analysis of the constituents of the postsynaptic density (PSD) proteome. PSD proteins were biochemically purified from amygdala/piriform cortex of VNS- or dummy-treated rats following 1-week stimulation, and individual PSD protein levels were quantified by liquid chromatography-tandem mass spectrometry analysis. We identified 1899 unique peptides corresponding to 425 proteins in PSD fractions, of which expression levels of 22 proteins were differentially regulated by VNS with changes greater than 150%. Changes in a subset of these proteins, including significantly increased expression of neurexin-1α, cadherin 13 and voltage-dependent calcium channel α2δ1, the primary target of the antiepileptic drug gabapentin, and decreased expression of voltage-dependent calcium channel γ3, were confirmed by western blot analysis of PSD samples. These results demonstrate that VNS modulates excitatory synapses through regulating a subset of the PSD proteome. Our study reveals molecular targets of VNS and point to possible mechanisms underlying its beneficial effects, including activity-dependent formation of excitatory synapses.
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影响因子：
5.3
作者：
Goussakov, IV;Fink, K;Beck, H
通讯作者：
Beck, H
影响因子：
5.6
作者：
Alexander, Georgia M.;McNamara, James O.
通讯作者：
McNamara, James O.
影响因子：
16.2
作者：
Huang, Yang Z.;Pan, Enhui;McNamara, James O.
通讯作者：
McNamara, James O.
影响因子：
16.2
作者：
Paradis, Suzanne;Harrar, Dana B.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
DOI：
10.1017/s1461145712000387
发表时间：
2013-03-01
影响因子：
4.8
作者：
Manta, Stella;El Mansari, Mostafa;Blier, Pierre
通讯作者：
Blier, Pierre