Research ArticleNeuroscience

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

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Science Signaling  18 May 2021:
Vol. 14, Issue 683, eabe4111
DOI: 10.1126/scisignal.abe4111

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Leptin strengthens synapses

Early-life malnutrition is associated with neurodevelopmental disorders. Sahin et al. found that leptin—a hormone produced by fat cells that induces the feeling of satiety—is critical for the development of inhibitory GABAergic synapses in the brain. In cultured hippocampal neurons from male and female rat pups, leptin enhanced the formation of a series of physical and functional protein interactions involving the leptin receptor, the guanine exchange factor (GEF) β-PIX, the kinase CaMK, and GABAA receptors that together resulted in increased abundance of GABAA receptors at the synapse. The findings reveal how leptin facilitates neuronal connectivity in the developing hippocampus and may provide clues in understanding and treating neurodevelopmental disorders.

Abstract

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 GABAA receptor–dependent synaptic currents in hippocampal neurons. Here, using molecular and electrophysiological techniques, we found that leptin increased the surface localization of GABAA receptors and the number of functional GABAergic synapses in hippocampal cultures from male and female rat pups. Leptin increased the interaction between GABAA 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.

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