Date of Graduation
Eberly College of Arts and Sciences
Miranda N Reed
A large body of clinical evidence suggests that viral infections in the periphery can exacerbate neurodegenerative conditions such as Alzheimer's disease, Huntington's, disease, Parkinson's disease, multiple sclerosis, and seizures. The underlying mechanisms of these conditions involve the activation of the acute phase response (APR), part of the innate immune system, which recognizes viral molecular patterns. As neighboring cells become infected, inflammatory mediators are released into the bloodstream and relayed to the central nervous system where they produce a "mirror" inflammatory response. To induce the APR, polyinosinic-polycytidylic acid (PIC), a viral mimetic, is commonly used. PIC produces a robust and transient increase in inflammatory factors in the brain, which modify neuronal networks leading to behavioral traits referred to as sickness behavior.;Recent evidence also reveals an increase in kainic acid-induced seizure hypersusceptibility in PIC-challenged animals. Although the underlying mechanisms for this seizure hypersusceptibility are not well known, inflammatory mediators produced in response to PIC can act on excitatory glutamate receptors resulting in increased neuronal activity. Increased neuronal activity has been implicated in many neurodegenerative conditions. To examine glutamate's role in the pathophysiology of seizures after peripheral insult, microelectrode arrays were employed to measure glutamate levels in the hippocampus of mice. In Experiment 1, female C57BL/6 mice were i.p. injected with PIC, and 24 hours later glutamate levels were measured in each subregion of the hippocampus (DG, CA3, and CA1). PIC-challenge resulted in a robust increase in resting extracellular glutamate levels. Although potassium-evoked glutamate release was similar between PIC and saline mice, glutamate clearance was significantly decreased after PIC-challenge. These results suggest functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC-challenged mice revealed an increase in basal synaptic transmission, increased probability of pre-synaptic glutamate release, and enhanced long-term potentiation (LTP). Altogether, these results reveal dysregulation of glutamate homeostasis and enhanced excitatory synaptic transmission, which could contribute to the seizure hypersusceptibility observed in PIC-challenged mice.;Experiment 1 characterized glutamate neurotransmission in an anesthetized animal after PIC injection, while Experiment 2 aimed to investigate the relationship between PIC challenge, glutamate homeostasis, and seizure severity in an awake behaving animal. MEAs were chronically implanted in the CA1 of the hippocampus to record tonic glutamate and glutamate transients, or spontaneous glutamate release before, during, and after KA-induced seizures across four days. Our results revealed an increase in tonic glutamate levels, an effect that gradually declined across the four days. These results are congruent with the decrease in seizure activity and inflammatory mediator levels across days. The most notable finding was that tonic glutamate levels were predictive of seizure severity as indicated by an increase in the average and cumulative seizure scores. The results provide greater insight into the mechanisms underlying the changes that occur during cerebral inflammation and may provide a link between peripheral insult and the comorbidity of neurodegenerative conditions.
Hunsberger, Holly C., "Effects of Anti-viral Acute Phase Response on Hippocampal Glutamate Regulation" (2016). Graduate Theses, Dissertations, and Problem Reports. 5839.