Developing hippocampal neurons undergo rapid synaptogenesis in response to neurotrophic signals to form and refine circuit connections. The adipokine leptin is a satiety factor with neurotrophic actions, which potentiates both glutamatergic and GABAergic synaptogenesis in the hippocampus during neonatal development. Brief exposure to leptin enhances GABA_A receptor–dependent synaptic currents in hippocampal neurons. Here, using molecular and electrophysiological techniques, we found that leptin increased the surface localization of GABA_A receptors and the number of functional GABAergic synapses in hippocampal cultures from male and female rat pups. Leptin increased the interaction between GABA_A receptors and the Rho guanine exchange factor β-PIX (a scaffolding protein at GABAergic postsynaptic sites) in a manner dependent on the kinase CaMKK. We also found that the leptin receptor and β-PIX formed a complex, the amount of which transiently increased upon leptin receptor activation. Furthermore, Tyr⁹⁸⁵ in the leptin receptor and the SH3 domain of β-PIX are crucial for this interaction, which was required for the developmental increase in GABAergic synaptogenesis. Our results suggest a mechanism by which leptin promotes GABAergic synaptogenesis in hippocampal neurons and reveal further complexity in leptin receptor signaling and its interactome.

发育中的海马神经元响应神经营养信号而经历快速突触形成，以形成和完善电路连接。脂肪因子瘦素是一种具有神经营养作用的饱腹感因子，可在新生儿发育过程中增强海马中的谷氨酸能和 GABA 能突触发生。短暂暴露于瘦素可增强海马神经元中 GABA _A受体依赖性突触电流。在这里，使用分子和电生理学技术，我们发现瘦素增加了雄性和雌性幼鼠海马培养物中 GABA _{A受体的表面定位和功能性 GABA 能突触的数量。瘦素增加 GABA A}之间的相互作用受体和 Rho 鸟嘌呤交换因子 β-PIX（GABA 能突触后位点的支架蛋白）以依赖激酶 CaMKK 的方式。我们还发现瘦素受体和 β-PIX 形成复合物，其数量在瘦素受体激活时瞬时增加。此外，瘦素受体中的 Tyr ⁹⁸⁵和 β-PIX 的 SH3 结构域对于这种相互作用至关重要，这是 GABA 能突触发生发育增加所必需的。我们的研究结果表明瘦素促进海马神经元中 GABA 能突触发生的机制，并揭示了瘦素受体信号传导及其相互作用组的进一步复杂性。