Dissertation
Extracellular cues shape GABAergic transmission in the developing hippocampus: The case of leptin
Doctor of Philosophy (PhD), Washington State University
01/2014
Handle:
https://hdl.handle.net/2376/5406
Abstract
The present dissertation tackles the larger question of how external cues, including sensory stimulation, neuronal activity, neurotrophins and soluble factors from the periphery (hormones) impact the development of the central nervous system. Our specific aim was to explore the effect of leptin, an adipocyte-derived hormone, on GABAergic plasticity in the developing rodent hippocampus. We used acute hippocampal slices of newborn rats to show that leptin induces a long lasting potentiation of the frequency of miniature GABAA receptor-mediated postsynaptic currents (LLP-GABAA), likely resulting from an increase in the number of functional GABAergic synapses. Using pharmacological tools we found that the leptin-induced LLP-GABAA requires a postsynaptic increase in calcium released from internal stores and the activation of PI3K, CaMKK and MEK1/2. In order to address the mechanistic action of leptin which mediates the observed GABAergic plasticity, we confirmed that leptin induces LLP-GABAA on dissociated hippocampal neurons, and began to develop a method to measure the morphological correlate of leptin-induced functional plasticity of GABAergic synapses in culture. Applying this method suggested that the leptin-induced LLP-GABAA might occur with a constant density of postsynaptic GABAA receptor puncta. Taken together, these data show that leptin induces a potentiation of GABAergic activity in developing hippocampal neurons, perhaps by recruiting clusters of GABAA receptors expressed at the membrane to form newly functional GABAergic synapses. In addition we found that CA3 pyramidal neurons of leptin-deficient ob/ob mice exhibit lower miniature GABAergic activity compared to wild type littermates, which suggests that leptin contributes to the development of the hippocampal GABAergic circuitry in vivo. Overall, these studies shed a new light on the development of admittedly "higher-level" cerebral regions which were found here to integrate "lower-level", peripheral signals to shape their development.
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Details
- Title
- Extracellular cues shape GABAergic transmission in the developing hippocampus
- Creators
- Damien Guimond
- Contributors
- Gary A Wayman (Advisor)Suzanne M Appleyard (Committee Member)Joseph W Harding (Committee Member)R. Lane Brown (Committee Member)Michael D Varnum (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 244
- Identifiers
- 99900581643101842
- Language
- English
- Resource Type
- Dissertation