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

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 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, Tyr 985 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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https://hal-amu.archives-ouvertes.fr/hal-03242708
Contributor : Christophe Pellegrino Connect in order to contact the contributor
Submitted on : Monday, May 31, 2021 - 11:23:09 AM
Last modification on : Tuesday, October 19, 2021 - 9:21:02 PM

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Gulcan Semra Sahin, Jose Luis Rodriguez-Llamas, Crystal Dillon, Igor Medina, Suzanne Appleyard, et al.. Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons. Science Signaling, American Association for the Advancement of Science, 2021, 14 (683), pp.eabe4111. ⟨10.1126/scisignal.abe4111⟩. ⟨hal-03242708⟩

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