Regional Variation in Striatal Dopamine Spillover and Release Plasticity.
Regional Variation in Striatal Dopamine Spillover and Release Plasticity.
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DOI：
10.1021/acschemneuro.9b00577
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发表时间：
2020-03-18
影响因子：
5
通讯作者：
Levitan, Edwin S.
中科院分区：
文献类型：
--
作者：
Walters, Seth H.;Shu, Zhan;Michael, Adrian C.;Levitan, Edwin S.
最近对轴突终末多巴胺的光学观察和用快速扫描循环伏安法(FSCV)测量的诱发多巴胺反应的动力学模型支持突触释放部位多巴胺扩散的局部限制。然而，这种扩散障碍如何影响突触和音量传递尚不清楚。在这里，通过用两侧都存在多巴胺转运体(DAT)的假设来取代先前关于多巴胺转运体(DAT)只存在于扩散屏障外侧的假设，弥补了先前动力学模型对刺激序列的拟合中的不足。这与已知的DAT的分布是一致的，在多巴胺释放部位附近没有显示明显的DAT自由区。然后展示了一种同时的多重拟合策略，使独特的模型拟合能够对在活体或大脑切片中获得的多组诱发的多巴胺FSCV反应进行拟合。这种数据分析技术首次允许计算从突触周围空间溢出的多巴胺的比例，以及其他参数，如多巴胺释放、释放可塑性和摄取。这一分析表明，多巴胺从其释放部位扩散明显受阻(τ=5 S)，但由于DAT活性，多巴胺反应迅速。此外，新的分析表明，摄取抑制剂可以在刺激序列中抑制多巴胺的释放，显然是通过耗尽可释放的库来实现的。提示持续摄取对维持正在进行的突触多巴胺释放至关重要，先前报道的以及本文中声称的某些摄取抑制剂初始多巴胺释放的增加可能是成瘾的一个重要机制。最后，脑地形图数据显示，扩散障碍是保守的，但在突触周围摄取、体积传递和释放可塑性在大鼠纹状体内存在差异。因此，开发了一种分析范式来量化以前未被测量的脑多巴胺能传递的特征，并揭示多巴胺突触之间的区域功能差异。
Recent optical observations of dopamine at axon terminals and kinetic modeling of evoked dopamine responses measured by fast scan cyclic voltammetry (FSCV) support local restriction of dopamine diffusion at synaptic release sites. Yet, how this diffusion barrier affects synaptic and volume transmission is unknown. Here, a deficiency in a previous kinetic model’s fitting of stimulus trains is remedied by replacing an earlier assumption that dopamine transporters (DATs) are present only on the outer side of the diffusion barrier with the assumption that they are present on both sides. This is consistent with the known distribution of DATs, which does not show obvious DAT-free zones proximal to dopamine release sites. A simultaneous multi-fitting strategy is then shown to enable unique model fits to sets of evoked dopamine FSCV responses acquired in vivo or in brain slices. This data analysis technique permits, for the first time, the calculation of the fraction of dopamine which spills over from what appears to be the perisynaptic space, as well as other parameters such as dopamine release, release plasticity, and uptake. This analysis shows that dopamine’s diffusion away from its release sites is remarkably hindered (τ = 5 s), but dopamine responses are rapid because of DAT activity. Furthermore, the new analysis reveals that uptake inhibitors can inhibit dopamine release during a stimulus train, apparently by depleting the releasable pool. It is suggested that ongoing uptake is critical for maintaining ongoing synaptic dopamine release, and that the previously reported and also herein claimed increase of the initial dopamine release of some uptake inhibitors might be an important mechanism in addiction. Finally, brain mapping data reveal that the diffusion barrier is conserved, but there are variations in perisynaptic uptake, volume transmission and release plasticity within the rat striatum. Therefore, an analysis paradigm is developed to quantify previously unmeasured features of brain dopaminergic transmission and to reveal regional functional differences among dopamine synapses.
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DOI：
10.1126/science.aat4422
发表时间：
2018-06-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Patriarchi T;Cho JR;Merten K;Howe MW;Marley A;Xiong WH;Folk RW;Broussard GJ;Liang R;Jang MJ;Zhong H;Dombeck D;von Zastrow M;Nimmerjahn A;Gradinaru V;Williams JT;Tian L
通讯作者：
Tian L
影响因子：
4.7
作者：
Salinas AG;Davis MI;Lovinger DM;Mateo Y
通讯作者：
Mateo Y
影响因子：
4.7
作者：
Kita, Justin M.;Parker, Lauren E.;Wightman, R. Mark
通讯作者：
Wightman, R. Mark
影响因子：
2.5
作者：
Cragg, SJ;Nicholson, C;Rice, ME
通讯作者：
Rice, ME
影响因子：
7.4
作者：
Nesbitt, Kathryn M.;Jaquins-Gerstl, Andrea;Skoda, Erin M.;Wipf, Peter;Michael, Adrian C.
通讯作者：
Michael, Adrian C.