Cyclic AMP-producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice.
Cyclic AMP-producing chemogenetic activation of indirect pathway striatal projection neurons and the downstream effects on the globus pallidus and subthalamic nucleus in freely moving mice.
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DOI：
10.1111/jnc.14331
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发表时间：
2018-06
影响因子：
4.7
通讯作者：
Zhou FM
中科院分区：
文献类型：
--
作者：
Bouabid S;Zhou FM
间接通路纹状体中棘投射神经元（iMSN）对运动和认知脑功能至关重要。这些神经元表达高水平的cAMP增加腺苷A2 a受体（A2 aRs）。然而，尚未确定cAMP产生对iMSN尖峰活性的潜在影响，并且在自由移动的动物中记录鉴定的iMSN具有挑战性。在这里，我们表明，在转基因小鼠表达cAMP生产G蛋白GS偶联设计师受体专门激活的设计师药物（Gs-DREADD）在iMSN中，在MSN中的基线尖峰放电是正常的，表明DREADD表达不影响这些神经元的正常生理。腹膜内（IP）注射DREADD激动剂氯氮平-N-氧化物（CNO; 2.5 mg/kg）增加了50%记录的MSN的尖峰放电。然而，CNO不影响Gs-DREADD阴性小鼠的MSN放电。我们还发现，CNO注射抑制Gs-DREADD阳性小鼠苍白球外段（GPe）神经元的锋电位放电，进一步表明CNO兴奋iMSNs。与间接途径中对尖峰放电的这些影响在时间上一致，CNO注射选择性地抑制D2 Gs-DREADD小鼠的运动。综上所述，我们的研究结果强烈表明，iMSN中cAMP的产生可以增加iMSN的尖峰活性并引起运动抑制，从而解决了一个长期存在的问题，即iMSN中产生cAMP的A2 aR的细胞功能。在这项研究中，我们使用化学遗传学技术来模拟腺苷A2 a受体激活，并选择性地增加cAMP的生产间接通路介质棘神经元（iMSN），同时监测其在自由移动的小鼠尖峰放电。我们的研究结果表明，通过腹腔注射氯氮平N-氧化物激活cAMP产生的Gs-DREADD兴奋iMSNs，导致苍白球外段（GPe）神经元锋电位放电的抑制和丘脑底核（ENE）神经元亚群的兴奋。这些影响导致运动活动的抑制。我们的研究结果与iMSN激活一致，并提供了关于iMSN中cAMP信号传导机制功能的重要见解。
The indirect pathway striatal medium spiny projection neurons (iMSNs) are critical to motor and cognitive brain functions. These neurons express a high level of cAMP-increasing adenosine A2a receptors (A2aRs). However, the potential effects of cAMP production on iMSN spiking activity have not been established, and recording identified iMSNs in freely moving animals is challenging. Here we show that in the transgenic mice expressing cAMP-producing G protein Gs-coupled designer receptor exclusively activated by designer drug (Gs-DREADD) in iMSNs, the baseline spike firing in MSNs is normal, indicating DREADD expression does not affect the normal physiology of these neurons. Intraperitoneal (IP) injection of the DREADD agonist clozapine-N-oxide (CNO; 2.5 mg/kg) increased the spike firing in 50% of the recorded MSNs. However, CNO did not affect MSN firing in Gs-DREADD negative mice. We also found that CNO injection inhibited the spike firing of globus pallidus external segment (GPe) neurons in Gs-DREADD positive mice, further indicating CNO excitation of iMSNs. Temporally coincident with these effects on spiking firing in the indirect pathway, CNO injection selectively inhibited locomotion in D2 Gs-DREADD mice. Taken together, our results strongly suggest that cAMP production in iMSNs can increase iMSN spiking activity and cause motor inhibition, thus addressing a long-standing question about the cellular functions of the cAMP-producing A2aRs in iMSNs. In this study, we used chemogenetic techniques to mimic adenosine A2a receptor activation and to increase cAMP production selectively in indirect pathway medium spiny neurons (iMSNs), while monitoring their spike firing in freely moving mice. Our results show that cAMP-producing Gs-DREADD activation by intraperitoneal injection of clozapine N-oxide excites iMSNs, causing an inhibition of globus pallidus external segment (GPe) neuron spike firing and an excitation of a subgroup of neurons in the subthalamic nucleus (STN). These effects lead to an inhibition of motor activity. Our results are consistent with iMSN activation and provide important insights about the function of the cAMP signaling mechanism in iMSNs.
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DOI：
10.1523/jneurosci.2192-08.2008
发表时间：
2008-10-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Berke JD
通讯作者：
Berke JD
DOI：
10.1038/npp.2008.144
发表时间：
2009-03
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
Azdad K;Gall D;Woods AS;Ledent C;Ferré S;Schiffmann SN
通讯作者：
Schiffmann SN
影响因子：
64.8
作者：
Barnes, TD;Kubota, Y;Graybiel, AM
通讯作者：
Graybiel, AM
影响因子：
3.4
作者：
Coffey, Kevin R.;Nader, Miles;West, Mark O.
通讯作者：
West, Mark O.
影响因子：
2
作者：
Inase, M;Li, BM;Tanji, J
通讯作者：
Tanji, J