Antioxidants in Normal and Epileptic Brain: Effect on Synaptic Plasticity, Neural Network Physiology, and Memory

The brain undergoes continuous changes in structure and function in response to internal and external stimuli. The hippocampus, crucial in spatial learning and declarative memory, undergoes synaptic plasticity-augmented neuronal activity generating elevated amounts of reactive oxygen species (ROS) which plays key roles in functional and structural plasticity. Thus, this doctoral dissertation will investigate the role of antioxidants in hippocampal synaptic plasticity, neural network physiology, and memory in normal and epileptic brains. The first part focuses on ascorbic acid (AA; a.k.a. vitamin C), well known for its cellular protection in environments of high oxidative stress. Even though physiological concentrations of AA in the brain are significant (0.2–10 mM), surprisingly little is known concerning the role of AA in synaptic neurotransmission under normal, non-disease state conditions. AA effects on neurotransmission, plasticity, and spontaneous network activity (i.e., sharp waves and high-frequency oscillations; SPW-HFOs), at the CA3-CA1 synapse, were examined using an extracellular multi-electrode array in in vitro mouse hippocampal slices. It was determined that under physiological conditions AA participates in the refinement of signal processing and memory formation through regulation of neurotransmission, plasticity, network activity, and by limiting pathologic excitability. The second part focuses on temporal lobe epilepsy (TLE), often comorbid with substantial cognitive impairment. Oxidative stress and reduced mitochondrial respiratory chain complex I (MRCI) function has been found in human TLE and a mouse model of TLE. The Kv1.1 knockout (KO) mice, a preclinical model of TLE, display cognitive deficits and reduced hippocampal long-term potentiation. Thus, the contribution of excessive mitochondrial ROS to impaired hippocampal-mediated memory in epileptic KO mice and if it can be rescued with a mitochondrial-targeted antioxidant were investigated. Our data indicate that mitochondrial superoxide contributes to hippocampal-dependent memory impairment in epileptic KO mice. Treatments specifically targeting mitochondrial superoxide indicate the impairment can be reversed (despite the presence of pathology).

Grantor dc:publisher

Creighton University

Year dc:date.issued

2023

Author dc:creator

• Heruye, Segewkal Hawaze

Advisor dc:contributor.advisor

• Simeone, Timothy A.

• Ascorbic Acid
• Long-term Potentiation
• Mitochondrial Respiratory Chain Complex I
• MitoQ
• Reactive Oxygen Species
• Sharp Waves-High Frequency Oscillations

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Repository record dc:identifier.uri

https://cdr.creighton.edu/handle/10504/154038

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/154038