Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.
Mice lacking NMDA receptors in parvalbumin neurons display normal depression-related behavior and response to antidepressant action of NMDAR antagonists.
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DOI：
10.1371/journal.pone.0083879
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Meletis K
中科院分区：
文献类型：
--
作者：
Pozzi L;Pollak Dorocic I;Wang X;Carlén M;Meletis K
重度抑郁症的潜在回路不平衡仍然未知，目前的治疗方法仍然不足以治疗一大群患者。氯胺酮（一种NMDA受体（NMDAR）拮抗剂）的快速抗抑郁作用的发现将多巴胺能系统与抑郁症联系起来。有趣的是，抑制性GABA能系统的功能障碍也被认为是抑郁症的基础，并且通过人类成像和抑郁症患者的尸检材料发现了与GABA能神经元相关的缺陷。表达小清蛋白（PV）的GABA能中间神经元通过体周抑制调节局部回路功能，并且其活性是NMDAR依赖性的，这为氯胺酮抗抑郁作用中NMDAR和抑制系统之间提供了可能的联系。因此，我们研究了PV中间神经元的NMDAR依赖性活性对抑郁样行为的发展以及对NMDAR拮抗剂的快速抗抑郁作用的反应的作用。我们使用了在PV神经元中特异性缺乏NMDA神经传递的突变小鼠（PV-Cre+/NR 1f/f），并分析了抑郁样行为和快感缺乏。为了研究单次给予NMDAR拮抗剂的急性和持续效应，我们建立了重复暴露于强迫游泳试验（FST）的行为范式。在重复的FST或突变小鼠的蔗糖偏好试验中，我们没有观察到行为反应的改变。此外，在突变型PV-Cre+/NR 1f/f小鼠中，对NMDAR拮抗剂给药的行为反应没有显著改变。我们的研究结果表明，NMDA依赖的神经传递PV神经元是不必要的调节抑郁样行为，此外，NMDAR对PV神经元不是一个直接的目标NMDAR诱导的氯胺酮和MK 801的抗抑郁作用。
The underlying circuit imbalance in major depression remains unknown and current therapies remain inadequate for a large group of patients. Discovery of the rapid antidepressant effects of ketamine - an NMDA receptor (NMDAR) antagonist – has linked the glutamatergic system to depression. Interestingly, dysfunction in the inhibitory GABAergic system has also been proposed to underlie depression and deficits linked to GABAergic neurons have been found with human imaging and in post-mortem material from depressed patients. Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit function through perisomatic inhibition and their activity is NMDAR-dependent, providing a possible link between NMDAR and the inhibitory system in the antidepressant effect of ketamine. We have therefore investigated the role of the NMDAR-dependent activity of PV interneurons for the development of depression-like behavior as well as for the response to rapid antidepressant effects of NMDAR antagonists. We used mutant mice lacking NMDA neurotransmission specifically in PV neurons (PV-Cre+/NR1f/f) and analyzed depression-like behavior and anhedonia. To study the acute and sustained effects of a single NMDAR antagonist administration, we established a behavioral paradigm of repeated exposure to forced swimming test (FST). We did not observe altered behavioral responses in the repeated FST or in a sucrose preference test in mutant mice. In addition, the behavioral response to administration of NMDAR antagonists was not significantly altered in mutant PV-Cre+/NR1f/f mice. Our results show that NMDA-dependent neurotransmission in PV neurons is not necessary to regulate depression-like behaviors, and in addition that NMDARs on PV neurons are not a direct target for the NMDAR-induced antidepressant effects of ketamine and MK801.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
DOI：
10.1073/pnas.0308455101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Jackson, ME;Homayoun, H;Moghaddam, B
通讯作者：
Moghaddam, B
影响因子：
10.6
作者：
MUSCAT, R;PAPP, M;WILLNER, P
通讯作者：
WILLNER, P
影响因子：
5
作者：
PAPP, M;MORYL, E
通讯作者：
MORYL, E
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH