Normal development of neuronal connections in the hippocampus requires neurotrophic signals, including the cytokine leptin. During neonatal development, leptin induces formation and maturation of dendritic spines, the main sites of glutamatergic synapses in the hippocampal neurons. However, the molecular mechanisms for leptin-induced synaptogenesis are not entirely understood. In this study, we reveal two novel targets of leptin in developing hippocampal neurons and address their role in synaptogenesis. First target is Kruppel-Like Factor 4 (KLF4), which we identified using a genome-wide target analysis strategy. We show that leptin upregulates KLF4 in hippocampal neurons and that leptin signaling is important for KLF4 expression in vivo. Furthermore, KLF4 is required for leptin-induced synaptogenesis, as shKLF4 blocks and upregulation of KLF4 phenocopies it. We go on to show that KLF4 requires its signal transducer and activator of transcription 3 (STAT3) binding site and thus potentially blocks STAT3 activity to induce synaptogenesis. Second, we show that leptin increases the expression of suppressor of cytokine signaling 3 (SOCS3), another well-known inhibitor of STAT3, in developing hippocampal neurons. SOCS3 is also required for leptin-induced synaptogenesis and sufficient to stimulate it alone. Finally, we show that constitutively active STAT3 blocks the effects of leptin on spine formation, while the targeted knockdown of STAT3 is sufficient to induce it. Overall, our data demonstrate that leptin increases the expression of both KLF4 and SOCS3, inhibiting the activity of STAT3 in the hippocampal neurons and resulting in the enhancement of glutamatergic synaptogenesis during neonatal development.

中文翻译：

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瘦素通过 KLF4 和 SOCS3 抑制 STAT3 信号传导刺激海马神经元中的突触发生。

海马神经元连接的正常发育需要神经营养信号，包括细胞因子瘦素。在新生儿发育过程中，瘦素诱导树突棘的形成和成熟，树突棘是海马神经元中谷氨酸能突触的主要部位。然而，瘦素诱导突触发生的分子机制尚不完全清楚。在这项研究中，我们揭示了瘦素在海马神经元发育中的两个新靶点，并探讨了它们在突触发生中的作用。第一个目标是 Kruppel-Like Factor 4 (KLF4)，我们使用全基因组目标分析策略确定了它。我们表明瘦素上调海马神经元中的 KLF4，并且瘦素信号传导对体内 KLF4 表达很重要。此外，瘦素诱导的突触发生需要 KLF4，因为 shKLF4 阻断和 KLF4 的上调表型复制它。我们继续表明 KLF4 需要其信号转导器和转录激活因子 3 (STAT3) 结合位点，因此可能会阻断 STAT3 活性以诱导突触发生。其次，我们表明瘦素增加了海马神经元发育过程中细胞因子信号抑制因子 3 (SOCS3) 的表达，SOCS3 是另一种众所周知的 STAT3 抑制剂。SOCS3 也是瘦素诱导的突触发生所必需的，并且足以单独刺激它。最后，我们表明组成型活性 STAT3 阻断了瘦素对脊柱形成的影响，而 STAT3 的靶向敲低足以诱导它。总的来说，我们的数据表明瘦素增加了 KLF4 和 SOCS3 的表达，