Basic Helix Loop Helix Enhancer 40 in Neuronal Excitability and Synaptic Plasticity
Date
2016
Authors
Hamilton, Kelly Andrew
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Abstract
This dissertation describes the role of the Basic helix loop helix enhancer 40 (Bhlhe40) transcription factor in the adult murine brain at the molecular, cellular, network, and behavioral levels. Studies for this dissertation were performed on a congenic Bhlhe40 gene knock out mouse model (Bhlhe40 KO). The inspiration for this research project was based on prior findings in mice that were genetically null for the Bhlhe40 gene on a mixed genetic background (Jiang et al., 2008, J. Neurosci). Mixed background Bhlhe40 KO mice had enhanced seizure activity when injected intraperitoneally with the convulsant, kainic acid (KA). In the hippocampus, brain derived neurotrophic factor (BDNF) expression is increased following seizure activity and is thought to lower the threshold for subsequent seizures, implicating BDNF in a positive feedback loop in epileptogenesis. Specifically, mixed background Bhlhe40 KO mice had elevated basal levels of Bdnf-4 transcripts, which are normally expressed in an activity-dependent manner. The central hypothesis of this research was that congenic Bhlhe40 KO mice would have enhanced responses to KA-induced seizures due to excessive levels of basal BDNF. It was further thought that there would be coincident increases in neuronal activity in hippocampal slices and increased expression of genes modulating neuronal excitability.
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Keywords
Neurosciences, Molecular biology, Genetics, Bhlhe40, Insulin Degrading Enzyme, Neuronal Excitability, Synaptic Plasticity