Popova Dina, Ágústsdóttir Arna, Lindholm Jesse, Mazulis Ulams, Akamine Yumiko, Castrén Eero, Karpova Nina N
Neuroscience Center, University of Helsinki, P.O. Box 56, 00790 Helsinki, Finland.
Neuroscience Center, University of Helsinki, P.O. Box 56, 00790 Helsinki, Finland.
Eur Neuropsychopharmacol. 2014 Jul;24(7):1162-74. doi: 10.1016/j.euroneuro.2014.04.002. Epub 2014 Apr 29.
The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.
抗抑郁药氟西汀可诱导视觉和恐惧网络中的突触可塑性，并促进神经回路的结构重塑，这对于响应环境刺激的经验依赖性可塑性至关重要。我们最近证明，成年小鼠长期服用氟西汀并结合消退训练可独立于环境减轻恐惧。恐惧条件反射和消退会改变恐惧回路中的兴奋性和抑制性传递。在本研究中，我们调查了氟西汀、消退训练或它们的组合是否会在条件小鼠的杏仁核、海马体和前额叶皮质的突触蛋白谱中产生不同的持久变化。我们确定，在水和氟西汀处理的小鼠中，消退训练可诱导突触素表达，并在整个恐惧网络中下调GluA1:GluA2比率，这表明存在一种与氟西汀无关的共同机制，通过消退训练增加突触传递并重新排列AMPA受体。与常见变化相反，在水和氟西汀处理的小鼠中，突触前囊泡神经递质转运体VGAT和Vglut1分别在消退训练后上调。在高冻结饮水量的小鼠中，皮质GABA转运体Gat1水平降低，这表明皮质抑制性突触处GABA溢出存在适应不良的增加。恐惧条件反射会降低，而在水和氟西汀处理的小鼠中，消退训练分别诱导GABA受体α1和α2亚基的表达。只有氟西汀与消退训练的组合可增强杏仁核和海马体中GluN2A的表达，这强调了该NMDA受体亚基在成功消除恐惧记忆中的作用。我们的发现提供了新的数据，可能有助于开发有益的药理学减恐治疗策略。
