Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal...

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.