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Duke University Dissertation Template The Role of Dysfunctional Subcortical Circuitry in Mouse Models of Developmental Disability by Michael F. Wells Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Guoping Feng, Supervisor ___________________________ Marc Caron ___________________________ James McNamara ___________________________ Anne West, Chair Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2015 ABSTRACT The Role of Dysfunctional Subcortical Circuitry in Mouse Models of Developmental Disability by Michael F. Wells Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Guoping Feng, Supervisor ___________________________ Marc Caron ___________________________ James McNamara ___________________________ Anne West, Chair Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2015 Copyright by Michael F. Wells 2015 Abstract Developmental disabilities, including intellectual disability (ID), attention- deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD), affect approximately 1 in 6 children in the United States. Attempts to produce treatment for developmental disabilities have been hampered by our current lack of understanding of the molecular mechanisms underlying these disorders. Advancements in genome sequencing and animal modeling technologies have proven to be an invaluable resource in the elucidation of potential disease mechanisms, with recent studies reporting novel mutations of the Ptchd1 and Shank3 genes in patients with developmental disabilities. Though these two genes have been proposed to play important roles in neural development, their function in the normal brain and defective behavioral output are poorly understood. In this dissertation, I characterize the circuit and behavioral dysfunction of the genetically-engineered Ptchd1 and Shank3 knockout mice. With respect to Ptchd1, I found that expression is developmentally enriched in the thalamic reticular nucleus (TRN), which is a group of GABAergic neurons serving as the major source of inhibition for thalamo-cortical neurons. Slice and in vivo electrophysiological experiments revealed that deletion of this gene in mice disrupts SK2 currents and burst firing mechanisms in the TRN, a region that has previously been shown to play an important role in sleep, attention, and cognition. Consistent with clinical findings, Ptchd1 knockout mice display behavioral phenotypes indicative of hyperactivity, attention deficits, motor dysfunction, hyperaggression, and cognitive impairment. Interestingly, attention-like deficits and hyperactivity iv are rescued by SK2 pharmacological enhancement, suggesting a potential molecular target for developing treatment. Shank3 knockout mice display ASD-like phenotypes, including social interaction deficits and repetitive behaviors. In addition, biochemical, electrophysiological, and morphological abnormalities were discovered in the medium spiny neurons (MSNs) of these mice. However, the exact neural circuits and cell types responsible for the autistic-like behaviors have not been identified. To address this important question, I developed a new conditional Shank3 knockout mouse. Importantly, the behavioral abnormalities reported in the original Shank3 knockout mice were recapitulated in this novel conditional Shank3 knockout mouse, indicating that this mouse may be useful for future pathway- specific dissections of ASD-like behaviors. Together, these two sets of studies not only provide mouse models for dissecting the function of PTCHD1and SHANK3 in normal and abnormal neural development, but also demonstrate a critical role for PTCHD1 in TRN neurons and SHANK3 in MSN cells and in the case of PTCHD1, identify potential cellular and circuit pathway targets for much-needed pharmacological intervention. v Dedication To my grandmother, Mercedes L. Montalvo v. de Valencia. vi Contents Abstract ................................................................................................................... iv List of Tables .......................................................................................................... xii List of Figures ........................................................................................................ xiii Acknowledgements .................................................................................................. xv Chapter 1. Introduction ............................................................................................ 1 1.1 Mouse models of psychiatric disease .............................................................. 3 1.1.1 The use of mice versus rats ....................................................................... 4 1.1.2 Commonly used mouse models of disease ................................................. 5 1.1.3 The role of mouse models in drug discovery ............................................. 7 1.2 Thalamo-cortical circuitry and developmental disorders ............................... 9 1.2.1 Structure and function .............................................................................. 9 1.2.2 Relevance to disease ................................................................................ 12 1.3 Basal ganglia circuitry and developmental disorders ................................... 14 1.3.1 Structure and function ............................................................................ 14 1.3.2 Relevance to disease ................................................................................ 16 1.4 Discussion .................................................................................................... 17 Chapter 2. Materials and Methods ......................................................................... 18 2.1 Production of genetically engineered mice ................................................... 18 2.2 Transcript and protein analysis ................................................................... 21 2.3 TRN electrophysiology ................................................................................ 25 2.4 Behavioral tests ........................................................................................... 26 2.5 Analysis of striatal MSNs ............................................................................ 36 Chapter 3. Initial characterization of Ptchd1 ......................................................... 38 vii 3.1 Introduction ................................................................................................. 39 3.1.1 Ptchd1 and human disease ...................................................................... 39 3.1.2 Structure of Ptchd1 ................................................................................. 40 3.2 Results ......................................................................................................... 43 3.2.1 Function of PTCHD1 protein ................................................................. 43 3.2.1.1 Attempts at generating PTCHD1 antibody ..................................... 44 3.2.1.2 PTCHD1 as a receptor for sonic hedgehog....................................... 46 3.2.2 Ptchd1 mRNA expression profile ............................................................ 49 3.2.2.1 Quantification of Ptchd1 developmental expression ......................... 51 3.2.2.2 TRN enrichment of Ptchd1 expression ............................................. 51 3.2.3 PTCHD1 expression profile in a knock-in mouse ................................... 52 3.2.3.1 Generation of Ptchd1-YFP mouse .................................................... 52 3.2.3.2 PTCHD1 is co-expressed with GAD67 in the TRN ......................... 52 3.2.3.3 PTCHD1 co-expresses with interneuron subtype-specific markers .. 55 3.3 Discussion .................................................................................................... 58 3.3.1 Unknown molecular function of PTCHD1 .............................................. 58 3.3.2 Ptchd1 developmental enrichment in TRN cells ..................................... 59 Chapter 4. Ptchd1 knockout mice as a model of thalamic reticular dysfunction and developmental disability ......................................................................................... 60 4.1 Introduction ................................................................................................. 61 4.1.1 Role of the TRN in attention and cognition ........................................... 61 4.1.2 TRN burst firing mechanisms ................................................................. 62 4.2 Results ......................................................................................................... 64 4.2.1 Generation of Ptchd1 conditional knockout mouse ................................ 64 viii 4.2.2 In vitro TRN dysfunction in Ptchd1 knockout mice .............................. 65 4.2.2.1 Reduced TRN burst firing in Ptchd1 KO slices ............................... 65 4.2.2.2 Weakened SK2 currents in Ptchd1 KO slices .................................. 67 4.2.2.3 Altered baseline intracellular calcium levels in Ptchd1 KO slices .... 67 4.2.3 In vivo TRN dysfunction in Ptchd1 knockout mice ............................... 68 4.2.3.1 Reduced TRN bursts in
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