Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures.
Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures.
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DOI：
10.1016/j.neuropharm.2016.09.011
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发表时间：
2016-12
影响因子：
4.7
通讯作者：
Duman RS
中科院分区：
文献类型：
--
作者：
Lepack AE;Bang E;Lee B;Dwyer JM;Duman RS
最近的临床前和临床研究表明，三种功能不同的化合物，NMDA受体通道阻滞剂氯胺酮，mGlu 2/3受体拮抗剂LY 341495和NMDA受体甘氨酸位点剂GLYX-13产生快速和持久的抗抑郁作用。此外，据报道，这些药物刺激脑中的ERK和mTORC 1信号传导。在这里，我们使用大鼠原代皮层培养神经元，以进一步研究这些药物的细胞作用。结果表明，低浓度的所有三种化合物以浓度和时间依赖性方式快速增加ERK的磷酸化和活化形式以及mTORC 1的下游靶标p70 S6激酶的水平。此外，每种化合物快速增加BDNF释放到培养基中。进一步的研究表明，BDNF释放的诱导以及磷酸化ERK的刺激被AMPA受体拮抗剂孵育阻断。对AMPA受体刺激的需求表明这些快速试剂的作用是活性依赖性的。这种可能性得到了研究的支持，研究表明，通过与GABAA受体激动剂蝇蕈醇孵育，神经元沉默完全阻断磷酸化ERK和BDNF的释放。最后，与每种药物孵育24小时增加神经元分支的数量和长度。总之，结果表明，这三种不同的快速作用的抗抑郁药增加ERK信号和BDNF释放的活性依赖性的方式，导致增加神经元的复杂性。需要进一步的研究来确定这些作用在培养的神经元和啮齿动物模型中的确切机制。
Recent preclinical and clinical studies demonstrate that three functionally different compounds, the NMDA receptor channel blocker ketamine, mGlu2/3 receptor antagonist LY341495, and NMDA receptor glycine site agent GLYX-13 produce rapid and long lasting antidepressant effects. Furthermore, these agents are reported to stimulate ERK and mTORC1 signaling in brain. Here we used rat primary cortical culture neurons to further examine the cellular actions of these agents. The results demonstrate that low concentrations of all three compounds rapidly increase levels of the phosphorylated and activated forms of ERK and a downstream target of mTORC1, p70S6 kinase, in a concentration and time dependent manner. In addition, each compound rapidly increases BDNF release into the culture media. Further studies demonstrate that induction of BDNF release, as well as stimulation of phospho-ERK is blocked by incubation with an AMPA receptor antagonist. The requirement for AMPA receptor stimulation suggests that the effects of these rapid agents are activity dependent. This possibility is supported by studies demonstrating that neuronal silencing, via incubation with the GABAA receptor agonist muscimol, completely blocks phospho-ERK and BDNF release by each agent. Finally, incubation with each drug for 24 hr increases the number and length of neuronal branches. Together, the results demonstrate that these three different rapid acting antidepressant agents increase ERK signaling and BDNF release in an activity dependent manner that leads to increased neuronal complexity. Further studies will be required to determine the exact mechanisms underlying these effects in cultured neurons and in rodent models.
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氟西汀在抑郁样小鼠中以区域依赖性方式调节 mTOR 信号传导。
影响因子：
4.6
作者：
Liu XL;Luo L;Mu RH;Liu BB;Geng D;Liu Q;Yi LT
通讯作者：
Yi LT
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
DOI：
10.1073/pnas.1505289112
发表时间：
2015-05-12
影响因子：
11.1
作者：
Dwyer, Jason M.;Maldonado-Aviles, Jaime G.;Duman, Ronald S.
通讯作者：
Duman, Ronald S.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
影响因子：
4.8
作者：
Lepack, Ashley E.;Fuchikami, Manabu;Duman, Ronald S.
通讯作者：
Duman, Ronald S.