BACKGROUND Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear. METHODS We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca2+) channels in heterologous expression systems were used to determine the modulation of Ca2+ channels by SSRIs. We tested the behavioral effects of SSRIs in the chronic behavioral despair model of depression both in the presence and in the absence of SERT. RESULTS SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca2+ channels and was independent of SERT. Furthermore, SSRIs protected both wild-type and SERT knockout mice from behavioral despair induced by chronic stress. Finally, long-term depression was facilitated in animals subjected to the behavioral despair model, which was prevented by SSRI treatment. CONCLUSIONS These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca2+ channels and synaptic plasticity independent of SERT. Thus, L-type Ca2+ channels might constitute an important signaling hub for stress response and for pathophysiology and treatment of depression.

中文翻译：

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抗抑郁药通过 L 型 Ca 2+ 通道的非血清素转运蛋白依赖性抑制来挽救应激诱导的突触可塑性破坏

背景技术长期突触可塑性是大脑动态适应外部刺激并调节突触强度并最终调节网络功能的基本能力。在抑郁症动物模型和患有重度抑郁症的人类中，它会因行为压力而失调。抗抑郁药已被证明可以在动物模型和人类中恢复被破坏的突触可塑性。然而，潜在的机制尚不清楚。方法我们研究了选择性血清素再摄取抑制剂 (SSRIs) 在野生型大鼠和血清素转运蛋白 (SERT) 敲除小鼠的海马脑切片中对突触可塑性的调节。异源表达系统中的重组电压门控钙 (Ca2+) 通道用于确定 SSRI 对 Ca2+ 通道的调节。我们在存在和不存在 SERT 的情况下测试了 SSRIs 在抑郁症的慢性行为绝望模型中的行为影响。结果 SSRIs 选择性抑制海马长期抑制。SSRIs 对长期抑郁的抑制是由电压激活的 L 型 Ca2+ 通道的直接阻断介导的，并且与 SERT 无关。此外，SSRIs 保护野生型和 SERT 基因敲除小鼠免受慢性压力引起的行为绝望。最后，在接受行为绝望模型的动物中促进了长期抑郁，而 SSRI 治疗可以防止这种情况。结论 这些结果表明，抗抑郁药通过调节 Ca2+ 通道和突触可塑性，保护突触可塑性和神经元回路免受压力的影响，与 SERT 无关。因此，