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The Role of Potassium Ion and Water Channels in an Animal Model Of The Role of Potassium Ion and Water Channels in an Animal Model of Multiple Sclerosis DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Peter Isaac Jukkola, B.S. Graduate Program in Biomedical Science The Ohio State University 2014 Dissertation Committee: Chen Gu, Advisor Brian Kaspar Amy Lovett-Racke John Oberdick Copyright by Peter Isaac Jukkola 2014 ABSTRACT Neuroinflammation and demyelination in multiple sclerosis (MS) lead first to neuronal dysfunction, then to the potential for neurodegeneration. Voltage-gated potassium ion channels have key roles in maintaining the resting membrane potential of a neuron in readiness for neurotransmission. This includes repolarization of the membrane following an action potential, which involves a depolarization event mediated by voltage-gated sodium channels. Myelin, the many-layered lipid sheath surrounding axons, is known to participate in molecular interactions with the axonal membrane to target ion channels to important, specialized locations along the axon. The water channel aquaporin-4 (AQP4), expressed in astrocyte endfeet, also plays an important role in maintaining ionic and fluid homeostasis in the neuronal environment. Because progression of disease and permanent disability in MS appears related to the degree of neuronal loss, neuroprotective treatments are needed in MS. Although a nonspecific Kv channel blocker is currently approved for symptomatic treatment of MS, it is not known to provide any neuroprotective effect, it has significant side effects, and its mechanism of action is not clear. In my dissertation research, I used two animal models of MS, chronic or relapsing-remitting experimental autoimmune encephalomyelitis (chEAE or rrEAE) to mimic progressive or relapsing- remitting MS, respectively, and to characterize the effect of inflammatory, demyelinating ii lesions upon the expression and localization patterns of AQP4 and key Kv channels. I found that Kv 1.2, expressed in myelinated axons in spinal cord (SC) white matter (WM), was redistributed in lesioned areas from its normal location at the juxtaparanode (JXP). The JXP localization could be recovered in remitting rrEAE, but not late chEAE. Kv 2.1, normally clustered on the soma and proximal dendrites of alpha motor neurons located in SC ventral gray matter (GM), was declustered and reduced in expression levels in EAE. Kv 2.1 expression recovered to a more normal pattern in remitting rrEAE, but not late chEAE. Kv 1.4 expression was markedly increased in EAE SCWM surrounding lesions in reactive astrocytes, and this effect was enhanced in remitting EAE but not late chonic EAE. AQP4 and other astrocyte proteins were upregulated in SCWM lesioned areas in EAE, but reactive astrocytes in other CNS regions showed varying patterns of protein expression. These changes may reveal compensatory or neuroprotective effects of ion and water channel expression and regulation in the CNS during neuroinflammatory disease. My studies pave the way for more detailed studies in this field to determine the regulatory mechanisms and functional consequences of channel alteration in response to disease. As these elements of channel biology are better understood, better-targeted therapies with fewer side effects can be developed for the treatment of neurobiological disorders such as MS. iii DEDICATION This document is dedicated to my wife Kristie and my children, Timothy, Adelyn, Johannah, and Samuel. Their love and support gave me the courage to pursue this course to completion. iv ACKNOWLEDGMENTS I am thankful to: Dr. Kevin M. Kelly for giving me my start in biomedical research and for encouraging me to pursue graduate studies; to Dr. Haiyan Fu and Dr. Amy Lovett- Racke for allowing me to rotate in their labs; to Dr. Ichiko Nishijima for her mentorship through my PhD candidacy exam; to my current mentor Dr. Chen Gu for challenging me to be my best; to my coworkers Dr. Mingxuan Xu, Dr. Yuanzheng Gu, and Dr. Joshua Barry for their support, companionship and the many procedures they taught me; to Paula Monsma and the OSU Neurobiology Imaging Core for maintaining the microscope facilities that played a large part in my studies; to my dissertation committee members Dr. Brian Kaspar, Dr. Amy Lovett-Racke, and Dr. John Oberdick; to the numerous faculty members who have contributed to my education; and to Nationwide Children’s Hospital and The Ohio State University for institutional support. v VITA May 1996 .......................................................Aliquippa Baptist Temple Academy 1996-1998 ......................................................Biological Science, Community College of Beaver County 1998-2000 ......................................................B.S., Biology, Geneva College 2001-2007…………………………………..Research Assistant/Sr. Research Assistant, Allegheny-Singer Research Institute 2007 to present ..............................................Graduate Research Associate, Department of Medicine, The Ohio State University Publications Barry J, Gu Y, Jukkola P, O’Neill B, Gu H, Mohler PJ, Thirtamara Rajamani K, and Gu C (2014). Ankyrin-G Directly Binds to Kinesin-1 to Transport Voltage-Gated Na+ Channels into Axons. Developmental Cell. Jan 27;28(2):117-31 Jukkola P, Guerrero T, Gray V, and Gu C. Astrocytes Differentially Respond to Inflammatory Autoimmune Insults and Imbalances of Neural Activity. Acta Neuropathologica Communications. 1:70 (23 October 2013) vi Barry J, Xu M, Gu Y, Dangel A, Jukkola P, Shrestha C, and Gu C (2013). Activation of Conventional Kinesin Motors in Clusters by Shaw Voltage-Gated Potassium Channels. Journal of Cell Science May 1;126(Pt 9):2027-41. Gardner A, Jukkola P, Gu C (2012). Myelination of rodent hippocampal neurons in culture. Nature Protocols. Sep 6;7(10):1774-82. Jukkola, PI, Lovett-Racke AE, Zamvil SS, Gu C (2012). K+ channel alterations in the progression of experimental autoimmune encephalomyelitis. Neurobiology of Disease. Aug;47(2):280-93. Kelly KM, Shiau DS, Jukkola PI, Miller ER, Mercadante AL, Quigley MM, Nair SP, Sackellares JC (2011). Effects of age and cortical infarction on EEG dynamic changes associated with spike wave discharges in F344 rats. Experimental Neurology Nov;232(1):15-21. Jukkola PI, Rogers JT, Kaspar BK, Weeber EJ, Nishijima I (2011). Secretin deficiency causes impairment in survival of neural progenitor cells in mice. Human Molecular Genetics. Mar 1;20(5):1000-7. DiRosario J, Divers E, Wang C, Etter J, Charrier A, Jukkola P, Auer H, Best V, Newsom DL, McCarty DM and Fu H (2009) Innate and adaptive immune activation in the brain of MPS IIIB mouse model. J Neurosci Res 87:978-990. Nair SP, Jukkola PI, Quigley M, Wilberger A, Shiau DS, Sackellares JC, Pardalos PM, Kelly KM (2008). Absence seizures as resetting mechanisms of brain dynamics. Cybernetics and Systems Analysis 44(5):664-72. vii Kelly KM, Kharlamov EA, Downey KL, Jukkola PI, Grayson DR (2008). Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction. Brain Research 1210: 29-38. Kelly KM, Jukkola PI, Kharlamov EA, Downey KL, McBride JW, Strong R, Aronowski J (2006). Long-term video-EEG recordings following transient unilateral middle cerebral and common carotid artery occlusion in Long–Evans rats. Experimental Neurology 201:495-506. Kharlamova EA, Jukkola PI, Schmitt KL, Kelly KM (2003). Electrobehavioral characteristics of epileptic rats following photothrombotic brain infarction. Epilepsy Research 56:185-203. Fields of Study Major Field: Biomedical Sciences Area of Research Emphasis: Biology of Neurological Disorders viii TABLE OF CONTENTS ABSTRACT ...................................................................................................................... II DEDICATION................................................................................................................. IV ACKNOWLEDGMENTS ............................................................................................... V VITA................................................................................................................................. VI TABLE OF CONTENTS ............................................................................................... IX LIST OF TABLES ........................................................................................................ XII LIST OF FIGURES ..................................................................................................... XIII CHAPTER 1: INTRODUCTION ................................................................................... 1 NEUROINFLAMMATION AND NEURODEGENERATION......................................................... 1 DEMYELINATION .............................................................................................................. 2 MULTIPLE SCLEROSIS ...................................................................................................... 3 NEUROPROTECTION .......................................................................................................... 4 ION CHANNELS IN NEUROTRANSMISSION .......................................................................... 5 ION AND WATER CHANNELS IN THE NEUROVASCULAR UNIT ............................................. 7 ASTROCYTE CHANNEL PROTEINS .................................................................................... 10 Water channel AQP4 ................................................................................................
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