NEUROTROPHIC ACTIONS OF LEPTIN IN THE DEVELOPING HIPPOCAMPUS

Tyler Bland

Leptin has neurotrophic actions in the hippocampus to increase synapse formation and stimulate neuronal plasticity. Leptin also enhance cognition and has anti-depressive and anxiolytic-like effects, two hippocampal dependent behaviors. Mice lacking expression of leptin have lower cortical volume and exhibit depressive-like behaviors, while leptin injections during early postnatal development can rescue the reduced cortical volume as well as abnormalities in hypothalamic neuronal projections. This suggests that some of leptin’s neurotrophic actions may occur during early brain development. Here we identify four molecules that interact with the leptin receptor (LepRb) and are necessary for leptin stimulated synapse formation. Our first study demonstrates that hippocampal LepRb is targeted to the lysosome degradation pathway, which is regulated by the ubiquitin signaling pathway. Furthermore, we show that leptin increases ubiquitin specific protease 8 (USP8) activity and gene expression, resulting in deubiquitination of LepRb, enhancing its surface expression and signaling in the hippocampus. Lastly, increased USP8 expression increases synapse formation in hippocampal cultures, and is required for leptin stimulated synapse formation. Another mechanism by which leptin effects synapse formation is through the enhancement of NMDA receptor function, yet the exact mechanism is not well understood. In our second study, we show that leptin increases NR2B Y1472 phosphorylation, enhancing its surface localization, which is mediated by the Src family kinase, Fyn. Inhibiting NR2B Y1472 phosphorylation with either a dominant negative Fyn mutant or an NR2B Y1472F mutant that lacks this phosphorylation site, blocks leptin stimulated synapse formation. Furthermore, we show that NR2B, Fyn, and the scaffolding protein RACK1 occur in a complex with LepRb, and that overexpression of Fyn or RACK1 is sufficient to increase synapse density, while knockdown of either protein inhibits leptin stimulated synapse formation. In conclusion, we expand our knowledge on the LepRb interactome and the mechanisms by which leptin stimulates synapse formation in the developing hippocampus. Understanding these mechanisms can provide a foundation for developing future treatments for obesity and the many neurological disorders associated with abnormal dendritic spine density and synapse loss.

NEUROTROPHIC ACTIONS OF LEPTIN IN THE DEVELOPING HIPPOCAMPUS

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