The Role of Orexin in Hippocampal Synaptic Plasticity and Neural Network Physiology in a Normal and Epileptic Brain
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Authors
Kostansek IV, Joseph Anthony
Issue Date
2023
Volume
Issue
Type
Thesis
Language
en_US
Keywords
Epilepsy , High Frequency Oscillation , Hippocampus , Long-term Potentiation , Orexin , Sharp Wave
Alternative Title
Abstract
Orexin-A and orexin-B are modulatory peptides produced by lateral hypothalamic orexin neurons. Orexin neurons project axons throughout the brain. Orexins, therefore, modulate a wide variety of physiological functions, important for this study, learning and memory. Two mechanisms of learning and memory are synaptic plasticity and neural network activity. Though the role of orexin in learning and memory is not fully known, orexins are implicated in having biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting learning and memory at supra- and sub-homeostatic levels. Epilepsy is associated with increased orexin concentration and cognitive dysfunction. It is unknown how orexins contribute to cognitive dysfunction in epileptic brains. Thus, this doctoral dissertation will investigate the role of orexins in hippocampal learning and memory correlates. These correlates, synaptic plasticity, and neural network physiology are investigated in normal and epileptic brains. Thus, the first part of this project aims to determine how orexins influence SPW-ripples. Here, we used multi-electrode array recordings at the Schaffer collateral-CA1 (SC-CA1) synapse in ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on SPW-ripples. When applied individually, 100nM of the orexin-1 receptor antagonist SB-334867 and 100nM of the orexin-2 receptor antagonist EMPA reduced SPW incidence, amplitude, and duration and decreased the incidence of ripples. This work reveals that endogenous orexins modulate SPW-ripples. The second part of this project uses the Kv1.1 knockout (KO) mouse model of temporal lobe epilepsy (TLE). This mouse model exhibits spontaneous recurrent seizures and impairments in synaptic plasticity and SPW-ripples. In KO mice, there is a 20% increase in the number of orexin neurons in the lateral hypothalamus. Additionally exogenous application of orexin to the hippocampus impairs synaptic plasticity. Here, we used multi-electrode array recordings in ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on impaired synaptic plasticity and SPW-ripples. 300 nM of a dual orexin receptor antagonist, TCS-1102, attenuated hyperexcitability at the KO SC-CA1 hippocampal synapse, and rescued impaired synaptic plasticity, indicating that orexin impairs synaptic plasticity in epileptic brains. Impaired SPW-ripples were not rescued through orexin antagonism. Taken together, the results of this project indicate that orexins modulate learning and memory through SPW-ripples and impair synaptic plasticity in epileptic brains.
Description
2023
Citation
Publisher
Creighton University
License
Copyright is retained by the Author.
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