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Potentiating M1 and Mglu1 Receptors to Modulate Prefrontal Cortical Dysfunction in Psychiatric Diseases

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Potentiating M1 and Mglu1 Receptors to Modulate Prefrontal Cortical Dysfunction in Psychiatric Diseases Potentiating M1 and mGlu1 receptors to modulate prefrontal cortical dysfunction in psychiatric diseases By James Thomas Michael Maksymetz Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmacology March 31st, 2020 Nashville, Tennessee Approved: P. Jeffrey Conn, Ph.D. Craig W. Lindsley, Ph.D. Brad A. Grueter, Ph.D. Roger J. Colbran, Ph.D. Sachin Patel, M.D., Ph.D. Copyright © 2020 by James Thomas Michael Maksymetz All Rights Reserved ii ACKNOWLEDGEMENTS There are countless people that have contributed scientifically and intellectually to the work described in this dissertation. First and foremost, I would like to sincerely thank my graduate mentor Dr. P Jeffrey Conn for all of his support and guidance. I am eternally grateful for the scientific, career, and life advice that Jeff has provided throughout my graduate career. I would also like to thank the members of my dissertation committee for their helpful feedback, for putting up with my ever-changing research directions, and for continuously supporting my scientific and career development. Thank you to all of the members of the Conn lab, past and present, who have made the last few years a blast, through the good and the bad. In particular, I would like to thank the other half of “Shames”, Sean Moran, for his friendship and for being a great sounding board for ideas, problems, and terrible jokes. I will forever believe that our endless, pedantic arguments were essential for getting through graduate school. I would also like to thank Max Joffe for being a great friend and an amazing mentor in the lab. His help scientifically with the work in this dissertation has been invaluable but he is also an amazing role model for young scientists; he will without a doubt be an extraordinary professor. I would like to thank Branden Stansley for selflessly accompanying me to Italy and Aspen, but particularly for contributing to the fear conditioning work in this dissertation. A special thank you to Brianna Li for being a great trainee and for the genotyping, staining, and behavior you did! Likewise, I would like to thank Samantha Yohn, Jordan Galbraith, and Ellen Reith for collaborating on behavioral studies. Thank you to Nellie Byun for running the phMRI experiments, to Carrie Jones for providing the GluN1 KD mice, and to Craig Lindsley and all the members of the VCNDD who synthesized and provided an endless assortment of VU compounds for these studies. I would be remiss not to thank Nicole Fisher for her camaraderie in lab, in the Pharmacology department, and especially when we served on the PhGSA together. To all of the other members of the Conn Lab and VCNDD that I worked closely iii with including Dan Foster, Mark Moehle, Shalini Dogra, Zixiu Xiang, Jerri Rook, Colleen Niswender, Rocco Gogliotti, Sheryl Vermudez, and many others: thank you for your support and feedback over the years. I would like to acknowledge the amazing friends and colleagues I have made throughout graduate school who will undoubtedly be incredibly successful in all their future endeavors. I would also not be where I am today without the constant support of my family, persisting through the convoluted and likely incredibly boring descriptions of what I do but always being there when I need to talk and supporting me through thick and thin. Finally, none of this would have been possible without the constant support of my amazing partner Stephanie who has been there for me through it all. Thank you so much. iv TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................. iii LIST OF FIGURES ........................................................................................................... vi Chapter I. Structure and function of the prefrontal cortex.............................................................. 1 1.1 PFC Macrocircuitry ........................................................................................................... 5 1.2 PFC Microcircuitry ...........................................................................................................13 1.3 Molecular mediators of neurotransmission .......................................................................22 1.4 Synaptic plasticity of neurotransmission ..........................................................................29 II. PFC dysfunction and novel treatment approaches ..................................................... 39 2.1 Posttraumatic stress disorder ..........................................................................................39 2.2 Schizophrenia ..................................................................................................................43 2.3 Targeting M1 muscarinic receptors for the treatment of psychiatric disorders ...................51 2.4 Targeting mGlu1 receptors for novel treatments of schizophrenia ....................................55 2.5 Outline of Current Studies ...............................................................................................61 III. M1 muscarinic receptors modulate fear-related inputs to the prefrontal cortex: implications for novel treatments of posttraumatic stress disorder................................ 63 3.1 Abstract ...........................................................................................................................63 3.2 Introduction ......................................................................................................................64 3.3 Materials and Methods ....................................................................................................66 3.4 Results ............................................................................................................................72 3.5 Discussion .......................................................................................................................87 IV. Metabotropic glutamate receptor subtype 1 potentiation enhances cortical inhibition to rescue schizophrenia-like physiological and behavioral deficits ................................ 92 4.1 Abstract ...........................................................................................................................92 4.2 Introduction ......................................................................................................................92 4.3 Materials and Methods ....................................................................................................95 4.4 Results .......................................................................................................................... 105 4.5 Discussion ..................................................................................................................... 126 V. Discussion and future directions ............................................................................. 130 5.1 M1 Muscarinic Receptors and PTSD .............................................................................. 130 5.2 mGlu1 receptors and Schizophrenia .............................................................................. 139 5.3 Conclusion ..................................................................................................................... 149 References .................................................................................................................. 151 v LIST OF FIGURES Page Figure 1: Structural differences between the human and rodent PFC. ...................................... 5 Figure 2: Thalamic and limbic projections to the prelimbic cortex .............................................. 7 Figure 3: Cortical interneurons can be subdivided into PV, SST, and 5HT3aR expressing subtypes ...................................................................................................................................16 Figure 4: Components of a glutamatergic synapse ..................................................................24 Figure 5: Components of a GABAergic synapse ......................................................................27 Figure 6: Examples of long term potentiation (LTP) and long term depression (LTD) of synaptic transmission ..............................................................................................................................32 Figure 7: Fear circuitry and pharmacological approaches to augment fear extinction ...............41 Figure 8: Summary of inhibitory deficits observed in the dlPFC of postmortem samples from schizophrenia patients ..............................................................................................................49 Figure 9: Muscarinic receptor distribution and molecular mechanisms relevant to the treatment of psychiatric disorders .............................................................................................................52 Figure 10: Localization of mGlu receptor subtypes.. .................................................................57 Figure 11: Muscarinic LTD in the PFC is input-specific ............................................................74 Figure 12: Viral injection sites and terminal expression of eYFP-tagged ChR2 in prefrontal cortex (PFC) slices ....................................................................................................................76 Figure 13: Input-Specific mAChR LTD is mediated
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