Date of Graduation

2014

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Gregory W Konat

Committee Co-Chair

Ariel Agmon

Committee Member

Rosana Schafer

Committee Member

Eric Tucker

Committee Member

Hanting Zhang

Abstract

Seizure syndromes are common neuropathologies associated with epilepsy, metabolic disturbances, stroke, traumatic brain injury, heat stroke, fatigue, drug overdose and several other conditions. Peripheral inflammatory conditions have emerged as important comorbid factors in seizures. We found that peripherally restricted acute phase response (APR) elicited by intraperitoneal (i.p.) injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), renders the brain hyperexcitable as seen from profoundly exacerbated kainic acid (KA)-induced seizures. This hypersusceptibility was protracted for up to 72 h. Neither blood plasma transfer from PIC challenged mice nor injection of two highly expressed blood cytokines, IL-6 and IFNbeta, were able to recapitulate the effects of PIC. We also found the hypersusceptible phenotype to be cyclooxygenase (COX)-independent. These results indicate that peripheral APR-induced seizure hypersusceptibility is reliant on the diffusion of a number of blood-borne inflammatory factors in a concentration-dependent manner.;To understand how peripheral challenge with PIC can alter neural excitability and lead to hyperexcitability, we profiled hippocampal gene expression. qRT-PCR revealed rapid upregulation of 23 genes encoding cytokines, chemokine and chemokine receptors and 12 genes encoding proteins related to glutamatergic and GABAergic neurotransmission generally within 6 h after PIC challenge. Moreover, the expression of ten microRNAs (miRs) was rapidly affected by PIC challenge, but their levels generally exhibited oscillating profiles over the time course of seizure hypersusceptibility. Further exploration into this robust polygenic response by microarray analysis identified 625 differentially expressed genes (DEGs) across 6, 24, and 48 h post-PIC challenge. The complement pathway was found to be the most robustly activated. qRT-PCR quantification verified temporal upregulation of the mRNA encoding eight complement components, i.e., C1qa, C1qb, C1qc, CfB, C2, C3, C4, and C6. Collectively, these results indicate that peripheral PIC challenge triggers an extensive genetic reprograming in the hippocampus that may play a causative role in the remodeling of neural circuits resulting in the hyperexcitable phenotype.

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