O'Leary Olivia F, Wu Xuefei, Castren Eero
Neuroscience Centre, University of Helsinki, Finland.
Psychoneuroendocrinology. 2009 Apr;34(3):367-81. doi: 10.1016/j.psyneuen.2008.09.015. Epub 2008 Nov 1.
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.
抗抑郁药物被认为可调节突触传递和结构。我们推测，如果在突触密度降低的条件下进行测量，抗抑郁药引起的突触及其相关蛋白的变化可能会更加明显。因此，在本研究中，我们检测了用抗抑郁药氟西汀长期治疗是否会改变接受卵巢切除术的啮齿动物海马中突触蛋白的表达，据报道该手术会降低大鼠海马CA1区的突触密度。我们使用蛋白质免疫印迹法，分别测量了与突触结构、强度和活性相关的蛋白在海马中的表达变化，即突触后致密蛋白95（PSD - 95）、α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸受体（AMPA - R）亚基GluR1和磷酸化突触素（Ser9）。我们发现，氟西汀治疗增加了去卵巢但未假手术大鼠海马中磷酸化突触素、PSD - 95和突触型GluR1（而非总GluR1）的表达。由于脑源性神经营养因子（BDNF）及其受体TrkB的信号传导可介导对抗抑郁药的行为反应并诱导神经元可塑性，我们通过使用过表达截短形式TrkB受体（TrkB.T1）的转基因小鼠模型，研究了TrkB信号传导对氟西汀诱导的突触蛋白表达变化的作用。氟西汀使去卵巢野生型小鼠海马中的PSD - 95有小幅但显著的增加，但在去卵巢TrkB.T1小鼠或假手术小鼠中未出现此现象。与大鼠不同，氟西汀在两种基因型中均未改变突触型GluR1的表达，也未逆转去卵巢诱导的海马磷酸化突触素的减少。综上所述，这些结果表明，长期氟西汀治疗可增加海马中突触蛋白的表达，且这些效应中至少有一些需要TrkB信号传导。此外，这些效应仅在去卵巢动物中观察到，因此表明氟西汀诱导的突触蛋白水平升高可能仅在海马突触连接受到干扰时才会发生或变得可检测到。
