Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: Role of BDNF signalling
Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: Role of BDNF signalling
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DOI：
10.1016/j.psyneuen.2008.09.015
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发表时间：
2009-04-01
影响因子：
3.7
通讯作者：
Castren, Eero
中科院分区：
文献类型：
--
作者：
O'Leary, Olivia F.;Wu, Xuefei;Castren, Eero
抗突触药物被认为可以调节突触传递和结构。我们假设，如果在突触密度降低的条件下测量，抗抑郁药诱导的突触及其相关蛋白的变化可能会变得更加明显。因此，在本研究中，我们研究了抗抑郁药氟西汀长期治疗是否改变了接受卵巢切除术的啮齿动物海马中突触蛋白的表达，据报道，卵巢切除术可降低大鼠海马CA 1区的突触密度。使用蛋白质印迹法，我们测量了与突触结构，强度和活动，即突触后密度蛋白95（PSD-95），α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA-R）亚基GluR 1和磷酸突触蛋白（Ser 9），分别海马表达的变化。我们发现氟西汀治疗增加了磷酸突触蛋白、PSD-95和突触GluR 1的表达，由于BDNF及其受体TrkB的信号传导可以介导对抗抑郁药的行为反应并诱导神经元可塑性，我们研究了TrkB信号传导对氟西汀的贡献，通过使用过表达TrkB受体（TrkB.T1）截短形式的转基因小鼠模型诱导突触蛋白表达的变化。氟西汀在卵巢切除的野生型小鼠中产生了海马PSD-95的小但显著的增加，但在卵巢切除的TrkB.T1小鼠或假手术小鼠中没有。与大鼠相反，氟西汀没有改变突触GluR 1的表达，也没有逆转卵巢切除术诱导的海马磷酸突触素减少。综上所述，这些结果表明，长期氟西汀治疗可以增加海马中的突触蛋白表达，并且这些作用中至少有一些需要TrkB信号传导。此外，这些作用仅在卵巢切除动物中观察到，因此表明氟西汀诱导的突触蛋白水平增加可能仅在海马突触连接受到干扰时发生或变得可检测。(C)2008爱思唯尔有限公司保留所有权利。
Antidepressant drugs have been suggested to regulate synaptic transmission and structure. We hypothesised that antidepressant-induced changes in synapses and their associated proteins might become more apparent if they were measured under conditions of reduced synapse density. Therefore, in the present study, we examined whether chronic treatment with the antidepressant, fluoxetine alters expression of synaptic proteins in the hippocampus of rodents that underwent ovariectomy, a procedure which reportedly decreases synapse density in the CA1 region of the rat hippocampus. Using Western blotting, we measured changes in hippocampal expression of proteins associated with synapse structure, strength and activity namely, postsynaptic density protein 95 (PSD-95), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) subunit GluR1 and phosphosynapsin (Ser9), respectively. We found that fluoxetine treatment increased expression of phosphosynapsin, PSD-95 and synaptic GluR1 (but not total GluR1) in the hippocampus of ovariectomized but not sham rats.Since BDNF and signalling at its receptor, TrkB, can mediate behavioural responses to antidepressants and induce neuronal plasticity, we investigated the contribution of TrkB signalling to fluoxetine-induced changes in synaptic protein expression by using a transgenic mouse model overexpressing a truncated form of the TrkB receptor (TrkB.T1). Fluoxetine produced a small but significant increase in hippocampal PSD-95 in ovariectomized wildtype mice but not in ovariectomized TrkB.T1 mice or sham mice. In contrast to rats, fluoxetine did not alter expression of synaptic GluR1 and did not reverse ovariectomy-induced decreases in hippocampal phosphosynapsin in either genotype. Taken together, these results suggest that chronic fluoxetine treatment can increase synaptic protein expression in the hippocampus and at least some of these effects require TrkB signalling. Moreover, these effects were only observed in ovariectomized animals, thus suggesting that fluoxetine-induced increases in synaptic protein levels might only occur or become detectable when hippocampal synaptic connectivity is perturbed. (C) 2008 Elsevier Ltd. All rights reserved.