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Nicotine and Integrin Linked Kinase Interplay Modulates Synaptic Plasticity Mechanisms Required for Memory

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Nicotine and Integrin Linked Kinase Interplay Modulates Synaptic Plasticity Mechanisms Required for Memory Nicotine and Integrin Linked Kinase Interplay Modulates Synaptic Plasticity Mechanisms Required for Memory by Fatimah Mohammed Aljadani A thesis submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Master of Science Auburn, Alabama December 12, 2015 Keywords: Memory enhancement, Nicotine, ILK, Akt, GSK3β, Cognitive dysfunction Copyright 2015 by Fatimah Mohammed Aljadani Approved by Vishnu Suppiramaniam, Chair, Professor of Drug Discovery and Development Murali Dhanasekaran, Associate Professor of Drug Discovery and Development Rajesh Amin, Assistant Professor of Drug Discovery and Development Abstract Integrin Linked Kinase (ILK) has been associated with forms of synaptic plasticity required for memory. Nicotine, at low-concentration improves memory but higher concentrations impart learning and memory deficits. The relationship between nicotine and ILK, with regards to learning and memory, has yet to be investigated. In this study, I demonstrate the effect of different concentrations of nicotine on ILK and subsequent downstream signaling using H-19 rat hippocampal cells. In addition, I also show the differential modulation of synaptic plasticity by varying concentrations of nicotine is due to altered expression and function of synaptic nicotinic receptors. Our results indicate that nicotine affects cell viability, modulates ILK activity, micro-spine formation, and long term potentiation. Furthermore, nicotine also differentially modulated extracellular signal regulated kinase 1/2 (ERK1/2) required for synaptic plasticity. My data provides a novel mechanism by which nicotine modulates synaptic transmission and plasticity required for learning and memory. ii Acknowledgments First of all, I thank Allah, the most merciful, for enabling and directing me to the right path, and giving me the ability to complete the requirements to fulfill this work. I express my sincere thanks and deep gratefulness to Dr. Vishnu Suppiramaniam, who gave me the opportunity to join in his lab. He has provided tremendous guidance and support. His passion for science and research always encouraged me to become a research scientist. I would like to thank my graduate committee members Drs. Murali Dhanasekaran, Rajesh Amin along with Dr. Vishnu Suppirmaniam for their generous cooperation, guidance, supervision, and providing me with the resources and time to make this possible. Also, I would like to thanks my colleagues in the lab, Subharajit Bhattacharya, Ahmed Alhowail, Dwipayan Bhattacharya, Jenna Bloemer, Daniel Katz and Manal Buabeid for their support, assistant and providing a friendly atmosphere during my study. I would like to extend my appreciation to all the faculty members, staff and fellow students at the Department of Drug Discovery and Development. I would also like to thank my family members who provided me with spiritual support to follow this academic goal. My mother Wafaa Salem, my father Mohammed Aljadani, and my brothers especially Sultan Aljadani who helped in this journey. Most importantly, I want to thank my husband, Abdullah Albishr, for his encouragement and patience during this time, allowing me to chase my dream. I am also gratefully thankful for my beautiful son Mohammed who always was bliss and happiness in my life. Finally, but not least, I iii would like to thank my friends, Amira Roshdy, Nadia Alqahtani, Wojain Alyamani, Motrefa Alyami, and Shatha Aldahri for their support during my study and making me feel at home in Auburn. ! iv! Table of Contents Abstract ..................................................................................................................... ii Acknowledgments ................................................................................................... iii List of Figures ........................................................................................................ viii List of Abbreviations ............................................................................................... ix Chapter I (Review of Literature) .............................................................................. 1 1.1. Integrin Structure and Function ............................................................. 1 1.2. Integrin Linked Kinase (ILK) ............................................................... 3 1.3. Synaptic Transmission in the Brain ....................................................... 4 1.3.1. Cholinergic System .................................................................. 6 1.3.2. Nicotinic Receptors .................................................................. 7 1.4. Long Term Potentiation .......................................................................... 8 1.5 Role of ILK in Neuronal and Synaptic Transmission ............................ 10 1.6. Diabetes, Memory and ILK .................................................................. 10 v 1.7. Alzheimer’s Disease and ILK ................................................................ 12 Chapter II (Materials and Method) ......................................................................... 14 2.1. Cell Culture .......................................................................................... 14 2.2. Nicotine Treatment ................................................................................ 14 2.3. MTT Assay ............................................................................................ 15 2.4. Western Blot Analysis ........................................................................... 15 2.5. Immunohistochemistry .......................................................................... 16 2.6. Animal ................................................................................................... 17 2.7. Single-channel Electrophysiology ......................................................... 18 2.8. Preparations of Acute Hippocampal Slices ............................................ 19 2.9. Extracellular Field Recordings .............................................................. 20 2.10. Statistics ............................................................................................... 21 Chapter III (Results) ............................................................................................. 22 3.1. Nicotine modulates cell proliferation in H-19 hippocampal cell line ... 22 ! vi! 3.2. Nicotine alters the expression of ILK .................................................... 23 3.3. Nicotine decreases the expression of T-Akt and the p-Akt ................... 23 3.4. Nicotine decreases the expression of T-Gsk3α/β but and p-Gsk3β ........ 24 3.5. Nicotine impacts micro-spine formation in hippocampal cell lines ....... 24 3.6. Nicotine differentially modulates single-channel properties of synaptic nicotinic receptors ......................................................................................... 25 3.7. Nicotine (in vivo) modulates ILK signaling, basal synaptic transmission and LTP ......................................................................................................... 25 3.7.1. Input/output curves ..................................................................... 26 3.7.2. Paired pulse facilitation (PPF) ..................................................... 27 3.8. Nicotine modulates ERK signaling ......................................................... 27 Chapter V (Discussion) ......................................................................................... 40 Chapter IV (Conclusion and Prospective) ............................................................ 46 References ............................................................................................................. 47 ! vii! List of Figure Figure 1.1 ................................................................................................................. 2 Figure 1.2 ................................................................................................................. 4 Figure 1.3 ................................................................................................................. 6 Figure 1.4 ................................................................................................................. 8 Figure 2.1 ............................................................................................................... 19 Figure 3.1 ............................................................................................................... 29 Figure 3.2 ............................................................................................................... 30 Figure 3.3 ............................................................................................................... 31 Figure 3.4 ............................................................................................................... 32 Figure 3.5 ............................................................................................................... 33 Figure 3.6 ............................................................................................................... 34 Figure 3.7 ............................................................................................................... 37 Figure 3.8 ............................................................................................................... 39 ! viii! List of Abbreviations AD Alzheimer’s Diseases AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid CaMKII
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