Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Susan L. Patterson

Second Advisor

Steven F. Maier

Third Advisor

Ryan K. Bachtell

Fourth Advisor

Robert Spencer

Fifth Advisor

Gregory Carey

Abstract

The goals of this research were to investigate the combined effects of aging and inflammation on brain-derived neurotrophin (BDNF) protein biology and BDNF-dependent synaptic plasticity in the hippocampus. For the past two decades neurotrophin research has generated a large body of evidence supporting the role for neurotrophins in facilitating multiple forms of synaptic plasticity and memory in the hippocampus. However, little is known about the effects that both aging and neuroinflammation may impose on these neurotrophin-related pathways.

To carry out the experiments in this study we utilized multiple models: (1) A rodent model of aging and inflammation using young (3-month-old) and aged (24-month-old) Fisher344/Brown Norway rat F1 crosses (F344xBN). An inflammatory response in the central nervous system (CNS) was peripherally-induced in these animals following an intraperitoneal (i.p.) injection of live E.coli. (2) A murine model of Alzheimer's disease (AD) with inflammation. APP/PS1 transgenic mice were given an i.p. injection of lipopolysaccharide (LPS) to induce an inflammatory response. (3) An in vitro model of AD and inflammation using a human neuroblastoma SH-SY5Y cell line that received treatment of amyloid beta protein (Aβ) and recombinant interleukin-1 beta (IL-1β). Data was collected using the following experimental methods: (a) hippocampal synaptoneurosomal fractionationation to enrich for synaptic proteins of interest; (b) co-Immunoprecipitation for protein-protein interactions in hippocampal tissue; (c) Western Blot to determine protein expression levels; (c) electrophysiology to measure LTP and LTD.

The results of these works indicated that the combination of aging and inflammation produce a shift in the ratio of BDNF protein isoforms (pro : mature); and this shift in the ratio of BDNF protein isoforms are consistent with a shift in hippocampal synaptic plasticity from LTP to LTD. Furthermore, these data showed that inflammatory markers have the capacity to act at the level of synapses to induce changes in BDNF protein expression, as well as normal synaptic events that include exocytosis and cell signaling. Recommendations from these findings suggest that further research examining the effects of aging and neuro-inflammation on hippocampal function may provide insight into the phenotypic symptomology associated with some neurodegenerative disorders, which include hippocampal dysfunction and memory impairments.

Comments

Sixth advisor: Michael Stowell.

Share

COinS