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Nicotinic Signalling and Neurosteroid Modulation in Principal Neurons of the Hippocampal Formation and Prefrontal Cortex

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Title: Nicotinic Signalling and Neurosteroid Modulation in Principal Neurons of the Hippocampal Formation and Prefrontal Cortex
Author: Chung, Beryl
Department: Department of Biomedical Sciences
Program: Biomedical Sciences
Advisor: Bailey, Craig
Abstract: Nicotinic signalling plays an important role in coordinating the response of neuronal networks in many brain regions. During pre- and postnatal circuit formation, neurotransmission mediated by nicotinic acetylcholine receptors (nAChRs) influences neuronal survival and regulates neuronal excitability, synaptic transmission, and synaptic plasticity. Nicotinic signalling is also necessary for the proper function of the hippocampal formation (HF) and prefrontal cortex (PFC), which are anatomically and functionally connected and facilitate higher-order cognitive functions. The decline or dysfunction in nicotinic signalling and nAChR function has been observed in various neurological disorders, and the disruption or alteration of nicotinic signalling in the HF and/or PFC can impair learning and memory. While the location and functional role of the α4β2* nAChR isoform has been well characterized in the medial portion of the PFC, this is not well-established in the HF. What is the role of α4β2* nAChRs in excitatory principal neurons of the HF during early development? Growing evidence suggests that the progesterone metabolite allopregnanolone (ALLO) plays a role in mediating the proper function of the HF and the PFC, and that it may also inhibit nAChR function. How mightALLO influence α4β2* nAChR function during early development and/or affect neuronal excitation within a living system? This thesis aims to develop a foundation towards understanding the role of α4β2* nAChR-mediated neurotransmission in principal neurons of the HF during development, and the role of ALLO in modulating α4β2* nicotinic receptor function during this period. In this thesis, I demonstrate that functional ⍺4β2* nAChRs are present in principal neurons of the developing mouse HF. The function of these receptors is developmentally regulated, and nicotinic excitation differs between male and female mice. I also demonstrate that ALLO negatively modulates α4β2* nAChR function in living neurons. I show for the first time that crosstalk between the membrane progesterone receptor complex and the nAChR likely facilitates the actions of ALLO to modulate nAChR function. The findings in this thesis present new insights on ⍺4β2* nAChR expression and function, while adding to our understanding of how these receptors may influence neuronal excitability, synaptic transmission, and synaptic plasticity during early development.
URI: http://hdl.handle.net/10214/12943
Date: 2018-04
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