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Neuroinflammation, Glutamate Regulation and Memory

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Neuroinflammation, Glutamate Regulation and Memory Neuroinflammation, Glutamate Regulation and Memory. DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Holly M. Brothers, M.A. Graduate Program in Psychology The Ohio State University 2013 Dissertation Committee: Gary G. Berntson, John P. Bruno, Phillip G. Popovich, and Gary L. Wenk Copyrighted by Holly Marie Brothers 2013 Abstract 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 ii 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 iii candidacy proposal, and Chapter 7 briefly summarizes the knowledge gained and highlights my contribution to the field. Figure 1. Thesis overview Chapters 2-6 examine microglia activation in a model of chronic neuroinflammation (Chapters 2-6) and in natural aging (Chapters 2 and 6). Chapter 2 investigates modulation of pre-synaptic glutamate release by caffeine, Chapter 3 examines neuroinflammation in the midbrain and brainstem, Chapter 4 explores attenuation of post- synaptic NMDAR activity by delayed memantine treatment, Chapter 5 demonstrates compensatory changes in extra-synaptic glutamatergic regulation in response to chronic neuroinflammation and Chapter 6 investigates augmentation of glutamate clearance by Ceftriaxone and Riluzole. iv Dedication To my great-grandma who inspired me to begin this work, to my grandpa who inspires me to do this work and to my daughter Adelina who inspires me to continue this work. Adelina, I hope you will follow your dreams and do what makes you happy. Grandma and Grandpa, thanks for always giving me so much love. Mom, thanks for believing that my work will make a difference. Gram and Dad, thanks for the moxie. Scott, thanks for being one of my best friends. John Bidwell, your curiosity sparks mine. Thank you to the Rosses for making me part of your family, Javy and Adelina for being my family, the Sotos for joining our family and thank you Isa, Roxanne and Sarah for making our lab like a family. v Acknowledgments Dr. Gary Wenk thank you for you incredible mentorship, I appreciate both your confidence and your criticisms greatly. Thanks Dr. Yannick Marchalant, Dr. Francesca Cerbai, Dr. Patricia Fernanda Schuck, Dr. Gustavo Ferriera, Dr. Åsa Konradsson-Geuken, Dr. Isabelle Bardou, Sarah Hopp, Roxanne Kaercher, Sarah Turner, Mollie Mitchem, Clelland Gash and David Bortz for teaching me and helping me to complete my experiments. Thanks Dr. Katrina Paumier and Dr. Daniel Ankeny for demonstrating stereological estimation, Dr. Kristina Kigerl for helping me test LPS on microglia culture, Dr. Angela Wynne Corona and Ashley Fenn for helping to test microglia using flow cytometry and Dr. Glenn Lin for sharing control tissue for GLT1 staining. Thanks to Dr. John Bruno, Dr. Jonathan Godbout and Dr. Phillip Popovich for sharing their equipment, students and post-docs. vi Vita 2001................................................................McKinley Sr. High School, Honors 2005................................................................Bachelor of Science, Honors in Arts and Sciences, Distinction in Psychology, Minor in Neuroscience, Magna Cum Laude, The Ohio State University 2005................................................................Phi Beta Kappa 2006 ...............................................................University Fellowship, The Ohio State University 2010 ...............................................................Master of Arts, Department of Psychology, The Ohio State University 2010 ...............................................................PhD Candidate, Department of Psychology, The Ohio State University 2011 ...............................................................University Presidential Fellowship, The Ohio State University Publications Cerbai F, Lana D, Nosia D, Petkova-Kirovab P, Zecchi S, Brothers HM, Wenk GL and Giovannini MG (2012). The neuron-astrocyte-microglia triad in normal brain vii ageing and in a model of neuroinflammation in the rat hippocampus. PLOS1, 7(9): e45250. Bardou I, DiPatrizio N, Brothers HM, Kaercher R, Baranger K, Mitchem M, Hopp SC, Wenk GL, Marchalant Y (2012). Pharmacological manipulation of cannabinoid neurotransmission reduces neuroinflammation associated with normal aging. Health, 1(4): 1-6. Norman GJ, Morris JS, Karelina K, Weil ZM, Zhang A, Al-Abed Y, Brothers HM, Wenk GL, Pavlov VA, Tracey KJ, DeVries AC (2011). Cardiopulmonary Arrest and Resuscitation Disrupts Cholinergic Anti-inflammatory Processes: A Role for Cholinergic α7 Nicotinic Receptors. J Neurosci, 31(9): 3446-52. Brothers HM, Marchalant Y, Wenk GL (2010). Caffeine attenuates lipopolysaccharide- induced neuroinflammation. Neuroscience Letters, 480(2): 97-100. Marchalant Y, Brothers HM, Wenk GL (2009). Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain. Molecular Psychiatry, 14(12): 1068-1071 and cover image. Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL (2009). Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiology of disease, 34(2): 300-7. Marchalant Y, Brothers HM, Wenk GL (2008). Inflammation and aging: can endocannabinoids help? Biomedicine and Pharmacotherapy, 64(4): 212-7. Knox D, Brothers HM, Norman G, Berntson GG (2008). Nucleus basalis magnocellularis and substantia inominata corticopetal cholinergic lesions viii attenuate freezing induced by predator odor. Behavioral Neurosci, 122(3): 601- 10. Marchalant Y, Cerbai F, Brothers HM, Wenk GL (2008). Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiology of Aging, 29(12): 1894-901. Marchalant Y, Brothers HM, Wenk GL (2008). Neuroinflammation in young and aged rats: influence of endocannabinoids and caffeine. Abstract. Journal of Neuroimmunology, 197(2): 168. Fields of Study Major Field: Psychology ix Table of Contents Abstract ............................................................................................................................... ii Dedication ..........................................................................................................................
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