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Activity-Dependent Modulation of Neuronal Sodium Channel Expression Joshua Peter Klein Yale University

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Activity-Dependent Modulation of Neuronal Sodium Channel Expression Joshua Peter Klein Yale University Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 5-2004 Activity-dependent modulation of neuronal sodium channel expression Joshua Peter Klein Yale University. Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Part of the Medicine and Health Sciences Commons Recommended Citation Klein, Joshua Peter, "Activity-dependent modulation of neuronal sodium channel expression" (2004). Yale Medicine Thesis Digital Library. 2198. http://elischolar.library.yale.edu/ymtdl/2198 This Open Access Dissertation is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. ACTIVITY-DEPENDENT MODULATION OF NEURONAL SODIUM CHANNEL EXPRESSION A Dissertation Presented to the Faculty of the Graduate School of Yale University in Candidacy for the Degree of Doctor of Philosophy by Joshua Peter Klein Dissertation Director: Stephen G. Waxman, M.D.,Ph.D. May, 2004 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACTiViTY-DEPENDENT MODULATION OF NEURONAL SODIUM CHANNEL EXPRESSION Joshua Peter Klein 2004 ABSTRACT Action potentials initiate via the voltage-dependent opening of plasma membrane-associated sodium channels. The number and type of sodium channels in a neuronal membrane determine the quantity of sodium current that results from a given stimulus. The expression of sodium channels in neurons is plastic, and is not only altered by injury and disease, but also by subtle changes in physiologic environment. In this dissertation, the effect of neuronal activity level on the expression and function of sodium channels is explored within several neuronal populations. First I examine the response of vasopressin-producing magnoceliuiar neurosecretory cells of the supraoptic nucleus to the hyperosmotic setting of chronic diabetes mellitus. Evidence for up- Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. regulation of sodium channels, and metabolic overactivation leading to apoptosis, in these neurons is presented. Second, ! test the effect of electrical stimulation on expression of sodium channels in cultured sensory neurons. And lastly, I demonstrate that there is dysregulated sodium channel expression within cortical neurons in a specific region of the brain in a model of absence epilepsy. Together, the results of these experiments support the hypothesis that the activity level of a neuron influences its rate of production and expression of sodium channels. Identification of this phenomenon could lead to new therapeutic strategies for 1) limiting end-organ pathogenesis in diabetes (by reducing magnoceliuiar neurosecretory cell sodium channel activity, thereby preventing chronically up-regulated vasopressin secretion), 2) treating pain (by using stimulation to normalize post-injury sodium channel expression and reduce neuronal hyperexcitability), and 3) treating epilepsy (by targeted modulation or block of seizure-initiating sodium channel activity). Development of novel therapeutic approaches will depend on further characterization of the regulatory feedback mechanism that links changes in neuronal activity level with modulation of sodium channel expression. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ABSTRACT i TITLE PAGE iii COPYRIGHT iv TABLE OF CONTENTS v LIST OF FIGURES AND TABLES vii LIST OF ABBREVIATIONS viii ACKNOWLEDGMENTS ix DEDICATION xi CHAPTER 1: INTRODUCTION 1.1 THE VOLTAGE-GATED SODIUM CHANNEL 1 1.2 PLASTICITY OF VGSC EXPRESSION IN INJURY AND DISEASE 2 1.3 ACTIVITY-DEPENDENT MODULATION OF VGSC EXPRESSION 4 1.4 SPECIFIC AIMS 6 CHAPTER 2: SODIUM CHANNEL EXPRESSION IN HYPOTHALAMIC OSMOSENSITIVE NEURONS IN EXPERIMENTAL DIABETES 2.1 SUMMARY 8 2.2 INTRODUCTION 9 2.3 MATERIALS AND METHODS 10 2.4 RESULTS 12 2.4.1 INDUCTION OF DIABETES 2.4.2 UP-REGULATION OF SODIUM CHANNEL MRNA AND PROTEIN 2.4.3 FUNCTIONAL CHANGES IN DIABETIC MNCS 2.5 DISCUSSION 18 CHAPTER 3: APOPTOSIS OF VASOPRESSINERGIC HYPOTHALAMIC NEURONS IN CHRONIC EXPERIMENTAL DIABETES MELLITUS 3.1 SUMMARY 21 3.2 INTRODUCTION 22 3.3 MATERIALS AND METHODS 24 3.4 RESULTS 26 3.4.1 MORPHOLOGICAL CHANGES OCCUR IN DIABETIC MNCS 3.4.2 CASPASE-3 EXPRESSION IS UPREGULATED IN DIABETIC MNCS 3.4.3 DNA FRAGMENTATION OCCURS IN DIABETIC MNCS Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.4.4 QUANTIFICATION OF TUNEL AND VASOPRESSIN STAINING 3.4.4 TUNEL AND VASOPRESSIN DO NOT COLOCALIZE 3.4.5 MICROGLIAL ACTIVITY IS ENHANCED IN DIABETIC MNCS 3.5 DISCUSSION 37 CHAPTER 4: PATTERNED ELECTRICAL ACTIVITY MODULATES SODIUM CHANNEL EXPRESSION IN SENSORY NEURONS 4.1 SUMMARY 42 4.2 INTRODUCTION 43 4.3 MATERIALS AND METHODS 45 4.4 RESULTS 49 4.4.1 EFFECT OF ELECTRICAL STIMULATION ON NEURON SURVIVAL 4.4.2 STIMULATION DOWN-REGULATES SODIUM CHANNEL PROTEIN 4.4.3 STIMULATION DOWN-REGULATES SODIUM CHANNEL MRNA 4.5 DISCUSSION 54 CHAPTER 5: DYSREGULATION OF SODIUM CHANNEL EXPRESSION IN A RODENT MODEL OF ABSENCE EPILEPSY 5.1 SUMMARY 57 5.2 INTRODUCTION 58 5.3 MATERIALS AND METHODS 59 5.4 RESULTS 64 5.4.1 SWD INCIDENCE INCREASES WITH AGE IN WAG/RIJ RATS 5.4.2 SODIUM CHANNEL MRNA IS UP-REGULATED IN EPILEPTIC CORTEX 5.4.3 SODIUM CHANNEL PROTEIN IS UP-REGULATED IN LAYERS ll-IV 5.4.4 SODIUM CHANNEL EXPRESSION PARALLELS SWD INCIDENCE 5.5 DISCUSSION 72 CHAPTER 6: CONCLUSIONS 6.1 ACTIVITY-DEPENDENT MODULATION OF VGSC EXPRESSION 76 6.2 MOLECULAR CHANGES WITHIN NEURONS IN THE DIABETIC BRAIN 76 6.3 STIMULATION-DEPENDENT PLASTICITY OF CGSC EXPRESSION 84 6.4 VGSC EXPRESSION AND EPILEPSY 87 6.5 CLINICAL PERSPECTIVES 89 REFERENCES 91 COPYRIGHT PERMISSIONS 112 V! Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES AND TABLES Table 1.1 Voltage-gated sodium channel (VGSC) a-subunits 2 Fig. 1.1 Activity-dependent modulation of VGSC expression: a model 5 Fig. 2.1 Vasopressin expression is up-regulated in diabetic neurons 14 Fig. 2.2 Sodium channel mRNA is up-regulated in diabetic SON neurons 15 Fig. 2.3 Sodium channel protein is up-regulated in diabetic SON neurons 16 Fig. 2.4 Sodium currents are increased in diabetic SON neurons 17 Fig. 2.5 Hyperglycemia, vasopressin, and nephropathy 19 Fig. 3.1 Chronic diabetes induces morphological changes in the SON 30 Fig. 3.2 Caspase-3 is up-regulated in the chronically diabetic SON 31 Fig. 3.3 TUNEL-positive neurons in the chronically diabetic SON 32 Fig. 3.4 Quantification of TUNEL-positive neurons in the diabetic SON 33 Fig. 3.5 TUNEL and vasopressin overlap in the chronically diabetic SON 34 Fig. 3.6 Microglial and astrocytic reactivity in the chronically diabetic SON 35 Table 3.1 Quantification of SON neuronal phenotype 36 Fig. 4.1 NGF withdrawal down-regulates Navi.8 and Navi.9 51 Fig. 4.2 Electrical stimulation down-regulates Navi .8 and Navi .9 protein 52 Fig. 4.3 Electrical stimulation down-regulates N avi.8 and N avi.9 mRNA 53 Fig. 5.1 EEG recordings of absence epileptic WAG/Rij rats 68 Fig. 5.2 Navl.1 and Navi.6 mRNA is up-regulated in the WAG/Rij cortex 69 Fig. 5.3 Navl.1 and N avi.6 are up-regulated in layer ll-IV cortical neurons 70 Fig. 5.4 Sodium channel dysregulation correlates to seizure incidence 71 Fig. 6.1 Neurologically “active” and “passive” responses to diabetes 78 Fig. 6.2 Neuronal activity level modulates VGSC expression 86 Fig. 6.3 Cause or effect: sodium channel expression and epilepsy 88 VII Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF ABBREVIATIONS AGE advanced glycosylation end-product BSA bovine serum albumin cAMP cyclic adenosine monophosphate CREB cAMP response element binding protein DAB diamlnobenzadlne hydrochloride DM diabetes mellitus DRG dorsal root ganglia GABA gamma-amlnobutyric acid GFAP glial fibrillary acidic protein GLUT glucose transporter EEG electroencephalogram IGF insulin-like growth factor LTD long term depression LTP long term potentiation MAP mitogen activating protein MNC magnoceliuiar neurosecretory cell NGF nerve growth factor NMDA N-methyl-D-aspartate NO nitric oxide NOS nitric oxide synthase PBS phosphate-buffered saline PGR polymerase chain reaction PKC protein kinase C PVN paraventricular nucleus SON supraoptic nucleus STZ streptozotocin SD standard deviation SE standard error SWD spike-wave discharge TUNEL terminal dUTP nick end labeling TTX tetrodotoxin VGSC voltage-gated sodium channel VP vasopressin WAG/Rij Wistar Albino Glaxo from Rijswijk WM white matter VIII Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENTS I would like to thank Stephen G. Waxman for giving me the opportunity to spend three wonderfully productive and enjoyable years in his laboratory. His encyclopedic knowledge of neurology has been inspiring and his encouragement and guidance have allowed me to pursue my work with enthusiasm and confidence. I thank my thesis committee, Hal Blumenfeld, Jeffery D. Kocsis, and Robert H. LaMotte, for their critical evaluations of my work, and for their helpful ideas and suggestions. 1 thank Joel A. Black and Sulayman D. Dib-Hajj for their constant support, advice, and expert assistance with my experimental work. My friends in the Waxman lab, Matthew J. Craner, Bryan C. Hains, Carl Y. Saab, Ellen K. Wittmack, Theodore R. Cummins, Lynda Tyrrell, Shujun Liu, Pam Zwinger, Cindy Cadoret, and Bart Toftness helped create a pleasant and cooperative working environment. I would like to thank R. Douglas Fields, Elisabetta Tendi, and members of the Fields Lab at the NIH, and Davender S. Khera, Hrachya Nersesyan, and members of the Blumenfeld lab at Yale, for their hard work on our collaborations.
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