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Cortical Influences on Cognitive and Respiratory CORTICAL INFLUENCES ON COGNITIVE AND RESPIRATORY DYSFUNCTION IN A MOUSE MODEL OF RETT SYNDROME By CODY JAMES HOWELL Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Advisor: David M. Katz Ph.D. Department of Neurosciences CASE WESTERN RESERVE UNIVERSITY May 2019 Case Western Reserve University School of Graduate Studies We hereby approve the dissertation of Cody James Howell candidate for the degree of Doctor of Philosophy Committee Chair............................................................ Heather T. Broihier, Ph.D. Committee Member........................................................... David M. Katz, Ph.D. Committee Member..................................................... Evan S. Deneris, Ph.D. Committee Member............................................................. Thomas E. Dick, Ph.D. February 12th 2019 *We also certify that written approval has been obtained for any proprietary material contained therein 2 Contents List of Figures ……………......................................................................................7 List of Tables .......................................................................................................10 Abstract................................................................................................................11 Preface…………………………....…………………………………………………….13 Chapter 1: Introduction.....................................................................................16 Rett Syndrome: Clinical Presentation..................................................................16 Methyl-CpG-binding protein 2 (MECP2) and Rett Syndrome..............................19 Mouse Models of Rett Syndrome.........................................................................23 Activity Mapping in the Mecp2 Mutant Brain........................................................31 The Medial Prefrontal Cortex...............................................................................39 Chapter 2: Chronic Intermittent Treatment with Low-dose Ketamine Reverses Dendritic Spine Deficits in a Mouse Model of Rett Syndrome…..55 Abstract................................................................................................................56 Introduction..........................................................................................................57 Methods...............................................................................................................59 Results.................................................................................................................62 Development of dendritic spine defects in the mPFC in Mecp2 mutant mice…..62 3 Ketamine rapidly stimulates phosphorylation of rpS6..........................................63 Ketamine rapidly stimulates dendritic spine growth in symptomatic Mecp2 mutant mice.....................................................................................................................64 Ketamine stimulates dendritic spine growth following repeated dosing in symptomatic Mecp2 mutant mice........................................................................65 Discussion...........................................................................................................66 Chapter 3: Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome...........................................................................................................77 Abstract................................................................................................................78 Significance Statement........................................................................................79 Introduction..........................................................................................................79 Methods...............................................................................................................81 Results.................................................................................................................86 DREADD expression in mPFC pyramidal neurons..............................................86 DREADD-positive fibers project to brain regions important for respiratory control and cue-dependent fear memory.............................................................88 Increasing mPFC pyramidal neuron activity restores normal respiration in Mecp2 mutants....................................................................................................89 4 DREADD activation of mPFC pyramidal neurons impacts downstream function in respiratory-related neurons................................................................90 DREADD activation of mPFC pyramidal neurons restores long-term Retrieval of auditory conditioned fear..................................................................92 Discussion............................................................................................................93 Chapter 4: Specific Activation of the mPFC Projection Circuitry targeting the Dorsal Midline Thalamus and Its Impact on Cue-Dependent Fear Conditioning Deficits in a Mouse Model of Rett Syndrome……………………………………………………………...……....107 Introduction……………………………………………………………..………....….108 Methods………………………………………………………….………....…………110 Results……………………….………....………………………………………..……112 DREADD expression in mPFC pyramidal neurons projecting to the dMT……..112 DREADD activation of mPFC pyramidal neurons projecting to the dMT enhances expression of LTM retrieval in Wt but not Mecp2 mutant mice……..112 Discussion..……………………….………....……………………………………….114 Chapter 5: Discussion and Future Directions………...……………………….119 Low-dose ketamine treatment in mouse models of Rett syndrome………....….120 5 Activation of the mPFC in mouse models of Rett syndrome………....………....128 Translational considerations………....………………………………………..……135 Bibliography…………………………………………………………………………140 6 List of Figures Chapter 1 Figure 1. Schematic of the human MECP2 gene including the most common point mutations in associated with Rett syndrome..................................51 Figure 2. The Mecp2 mutant brain displays altered neuronal activity compared to wild-type………………………………………………..........................52 Figure 3. Model circuitry demonstrating the role of mPFC in respiration...............53 Figure 4. Model circuitry underlying cue-dependent fear conditioning……………54 Chapter 2 Figure 1. Dendritic spine density and maturity is reduced on apical oblique dendrites in the mPFC Mecp2 Null mice compared to Wt at 6 weeks of age……………………………………………………………………….…70 Figure 2. Dendritic spine maturity is reduced on apical oblique dendrites in the mPFC Mecp2 Null mice compared to Wt at 3 weeks of age…………….…71 Figure 3. The ratio of phospho-S6 (pS6) to total S6 is markedly reduced in the Mecp2 Null mPFC compared to Wt and is rescued by acute treatment with ketamine…………………………………………………………….…72 7 Figure 4. Mushroom spine deficits on oblique dendrites in the Mecp2 Null mPFC are rescued by either single acute treatment or chronic intermittent treatment with ketamine 24 hours after dosing……………………….73 Supplemental Figure 1. Same data set as shown in Figure 4, including segments removed as statistical outliers……………………….………………...…74 Chapter 3 Figure 1. DREADD-Gq expression in the mPFC…………………..………………98 Figure 2. Activation of mPFC pyramidal neurons by DREADD-Gq increases neuronal activity in vivo…………………………………………….……100 Figure 3. Photomicrographs showing mCherry-positive fibers in coronal sections through brain regions important for respiratory control and cue- dependent fear memory following DREADD-Gq infection of the mPFC...……101 Figure 4. DREADD-Gq activation of pyramidal neurons in the mPFC eliminates the apneic breathing phenotype in Mecp2 mutants..………………..102 Figure 5. Activation of pyramidal neurons in the motor cortex by DREADD-Gq does not alter respiration……………………………..……………..103 Figure 6. DREADD-Gq activation of pyramidal neurons in the mPFC reduces respiratory frequency variability to Wt levels without impacting 8 the average frequency of respiration.…………………….………………………..104 Figure 7. Activation of mPFC pyramidal neurons by DREADD-Gq impacts neuronal function in respiratory subnuclei of the nTS……………………………105 Figure 8. Activation of mPFC pyramidal neurons by DREADD-Gq rescues long-term expression of cue-dependent fear memory……………………………106 Chapter 4 Figure 1. Representative images from the mPFC and dMT demonstrating CRE-dependent DREADD-Gq and CRE expression respectively…………..….116 Figure 2. Preliminary data suggests that activation of mPFC projection neurons that target the dMT increases LTM expression in Wt but not in Mecp2 mutant mice………………………………..…………………………………117 Figure 3. Mecp2 Hets display increased CRE-dependent DREADD-Gq expression in the mPFC but reduced LTM retrieval response to stimulation of mPFC to dMT projection neurons………………………………..……………..118 9 List of Tables Table 1. Raw values for dendritic spine density listed for each spine type in either 6-week old or 3-week old Wt or Null mPFC………………………….……75 Table 2. Raw values for dendritic spine density listed for each spine type in 6-week old Wt and Null mPFC treated with either saline or one of three ketamine paradigms…..……………………...………………………………………..76 10 Cortical Influences on Cognitive and Respiratory Dysfunction in a Mouse Model of Rett Syndrome Abstract By CODY JAMES HOWELL A fundamental goal of neuroscience is to understand how behavior is controlled
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