NEUROTROPHIC ACTIONS OF LEPTIN IN HIPPOCAMPAL SYNAPTOGENESIS DURING DEVELOPMENT

Gulcan Semra Sahin

Leptin is a crucial neurotrophic factor during the development of the hippocampus. Mouse models that are deficient in leptin synthesis or functional leptin receptors exhibit depression, anxiety, and cognitive deficits, the disorders partly associated with impairments in hippocampal functioning. Interestingly, children with neurodevelopmental disorders such as autism spectrum disorder and Rett syndrome, have higher leptin levels than healthy children. It is mostly accepted that imbalance in excitatory/inhibitory synaptic transmission is one of the major contributors to these neurodevelopmental disorders. Accordingly, presence of elevated leptin levels in these disorders is very interesting as leptin is a positive regulator of both glutamatergic and GABAergic synaptic transmissions in the hippocampal neurons during development. However, the underlying signaling mechanisms of leptin’s actions are not completely understood. In this dissertation, I identify novel molecular pathways through which leptin induces glutamatergic and GABAergic synaptogenesis. In my first study, I report that chronic leptin exposure (3-4 days) increases glutamatergic synaptogenesis by upregulating the expression of both Kruppel-Like Factor 4 (KLF4) and Suppressor of Cytokine Signaling 3 (SOCS3) in the hippocampal neurons. I show that knockdown of either KLF4 or SOCS3 blocks the leptin-induced glutamatergic synaptogenesis, while overexpression of either of them is enough to induce glutamatergic synaptogenesis. Further, I show that Signal Transducer and Activator of Transcription 3 (STAT3), whose activity is suppressed by both KLF4 and SOCS3, is a negative regulator of leptin-induced glutamatergic synaptogenesis . In my second study, I show that acute leptin exposure (2-4 hours) induces GABAergic synaptogenesis at both morphological and functional level. I report that one of the regulators of the actin cytoskeleton, namely Rho guanine exchange factor β-PIX, mediates the effects of leptin on GABAergic synaptogenesis. I show that leptin receptor and β-PIX are in a complex, and their interaction transiently increases upon leptin receptor activation, and that is required for leptin-induced increase in GABAergic synaptogenesis. In conclusion, these studies will advance our knowledge on leptin’s actions in both glutamatergic and GABAergic synaptogenesis during hippocampal development. As we gain more insight into its actions, we will understand the roles of leptin in neurodevelopment disorders better.

NEUROTROPHIC ACTIONS OF LEPTIN IN HIPPOCAMPAL SYNAPTOGENESIS DURING DEVELOPMENT

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