Neuroinflammation, Glutamate Regulation and Memory

Neuroinflammation and excessive glutamatergic signaling have deleterious effects in the brain, are mutually promoting, and play a role in the onset and progression of neurodegenerative diseases. It was my goal to better understand the relationship between neuroinflammation, glutamate dysregulation and clinical symptoms, as well as identify potential therapeutic targets. To do this, I studied molecular, cellular and behavioral outcomes across various time points in young rats with experimentally-induced chronic neuroinflammation and older rats with age-associated neuroinflammation. I focused on Alzheimer’s (AD) and Parkinson’s (PD), and tested only treatments that had therapeutic potential in a clinical setting. These studies led to a number of important discoveries, summarized below. I first investigated the effects of reducing pre-synaptic glutamate release by caffeine treatment, and discovered that caffeine attenuated experimentally-induced but not age-associated neuroinflammation and was not sufficient to improve cognitive performance (Chapter 2). During these investigations, I discovered that young rats with experimentally-induced neuroinflammation reared on their hind legs less, a behavioral change associated with PD. Therefore, I next expanded the scope of my studies to include a thorough investigation of brain systems that degenerate in PD, the basal ganglia and brainstem, using our model of chronic neuroinflammation (Chapter 3). I found that neuroinflammation drives changes that indicate a decline in neurotransmitter production and function, and that all these changes recovered over time, despite the continued presence of a neuroinflammatory stimulus. I paralleled these investigations in the hippocampus, a region that degenerates in AD, while gathering preliminary data on delayed treatment with memantine, a drug which reduces post-synaptic glutamate function that is used for AD (Chapter 4). Like the basal ganglia and brainstem, I found compensatory recovery in hippocampal function over time, despite continued neuroinflammation, as revealed by recovery of cognitive performance in a hippocampal-sensitive behavioral task. These results were particularly interesting because delayed treatment with memantine, a drug which prevents AD-like cognitive decline under neuroinflammatory conditions, worsened performance in rats that would have otherwise recovered. This indicated that delayed reduction of post-synaptic glutamate interferes with a naturally occurring compensatory response. I speculated that this compensation was likely in the glutamatergic system and, if understood, could be augmented pharmacologically and become a therapeutic drug target for AD patients. Therefore, I investigated indicators of pre-, post- and extra-synaptic glutamatergic function, and discovered that recovery from AD-like memory decline correlated with a protein that clears excessive glutamate from the synapse, GLT1 (Chapter 5). In response to this discovery, I investigated whether two drugs that increase glutamate clearance would prevent AD-like cognitive decline in aged rats or young rats with experimentally-induced neuroinflammation (Chapter 6), and found that the drugs had modest, but beneficial effects on neuroinflammation and cognition. This document is a compilation of the projects outlined above (Figure 1). Chapter 1 is a thorough review of background material, Chapters 2-6 describe each project in a journal article format, Chapter 6 contains the final series of studies described in my candidacy proposal, and Chapter 7 briefly summarizes the knowledge gained and highlights my contribution to the field.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Psychology

Grantor dc:publisher

The Ohio State University

Year dc:date

2013

Author dc:creator

• Brothers, Holly M.

Contributors dc:contributor

• Wenk, Gary

• Neurosciences
• microglia
• inflammation
• astrocytes
• IL-1
• inflammatory
• EAAT2
• GLT1
• glutamate transport
• hippocampus

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=osu1363603410

OAI identifier oai:identifier

oai:etd.ohiolink.edu:osu1363603410