Semester

Fall

Date of Graduation

2019

Document Type

Dissertation

Publication Pending

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Gregory Konat

Committee Member

Candice Brown

Committee Member

Jason Huber

Committee Member

Rosana Schafer

Committee Member

James Simpkins

Abstract

Peripheral viral infections are po­tent comorbid factors that exacerbate neuro­degene­ration. Although the under­lying mecha­nisms have not been defined, neuronal hyperexcitability has been established as an underlying feature. Our lab has developed a preclinical model in which a viral mimetic, poly­inosinic-poly­cytidylic acid (PIC) is injected in­tra­peritoneally to induce an anti-viral acute phase response (APR). APR in turn elicits robust neuronal hyperexcitability. The present study was undertaken to characterize molecular mechanisms that mediate the development of hyperexcitability in response to PIC challenge. The analysis of brain tissue after PIC challenge revealed a robust elevation of CXCL10 chemokine, indicating its putative role in the process. We have further shown that CXCL10 is overwhelmingly produced by neurons. Neurons also express the cognate receptor, CXCR3, indicating that the CXCL10/CXCR3 axis acts in an autocrine/paracrine manner. Intracerebroventricular injection of CXCR3 inhibitor, AMG-487, abrogates PIC challenge-induced development of hyperexcitability, indicating that the CXCL10/CXCR3 axis drives this process. Moreover, CXCR3 signaling activates microglia. Because microglia are potent modulators of synaptic activity, they likely mediate the development of hyperexcitability. Accordingly, we posit that CXCL10/CXCR3 axis induces the generation of neuronal factors that activate microglia. Activated microglia in turn, impede the activity of inhibitory synapses. This de-inhibition results in the hyperexcitability of neuronal networks. Our results provide a springboard for the full elucidation of the underlying mechanisms that would facilitate the development of novel therapeutic modalities to combat the co-morbidity of peripheral viral infections in neurodegenerative diseases.

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