Astrocytes of the primate: form and function in health and disease Restricted; Files Only

Abstract

Astrocyte morphology and function is affected in most neurodegenerative disorders. Investigation into the neurobiological mechanisms underlying astrocyte morphological and functional changes remains in its infancy and has great potential to identify new targets for biomarkers and therapeutics. Of note, species differences in astrocyte morphology and function have been described though not comprehensively assessed, which may complicate our understanding of astrocytes in health and disease. Here, we narrowed this gap in knowledge by using a combination of histological techniques, electrophysiology, and pharmacology to assess astrocyte morphology and interrogate function to broadly improve our understanding of primate astrocytes, with particular relevance to parkinsonism. We examined how astrocyte morphology and interaction with surrounding structures differed between healthy mice and rhesus macaques. Primate astrocytes displayed larger territories with lower density of branches, but primate and mouse astrocytes covered a comparable number of synaptic terminals. Our data suggest that astrocyte complexity scales with size to optimally cover the neuropil across species. We also found species-specific morphological differences between mouse and primate astrocytes in the external globus pallidus (GPe), an astrocyte-enriched structure which displays astrocyte dysfunction in mouse models of parkinsonism. Next, we assessed astrocyte morphology in a primate model of parkinsonism. Our data suggest that astrocytes display morphological changes in parkinsonian primates, such as decreased territory areas, but do not display signs of astrocytic reactivity common to other neurodegenerative disorders. We also assessed expression and localization of connexin-43 (cx-43), a gap junction protein which is highly expressed in the GPe and increased in animal models of parkinsonism. Though cx-43 expression was not increased in parkinsonian primates, we did see increased localization to astrocyte endfeet. Finally, we examined how pharmacological manipulation of cx-43 affects pathological neuronal activity in the GPe of parkinsonian primates. Blocking astrocyte cx-43 further exacerbated some of the electrophysiological features of parkinsonism, which together with increased cx-43 expression in astrocyte endfeet, could indicate altered glio-vascular interactions following dopamine depletion. Together, these studies provide new information about astrocytes across species and highlight the importance of investigating astrocyte morphology and function in primate species to better understand their contribution to human disease.  

Table of Contents

CHAPTER 1: Introduction........................................................................................................... 1

1.1.................. CONTEXT............................................................................................................. 2

1.2.................. ASTROCYTES: A HISTORICAL PERSPECTIVE......................................... 2

1.3.................. ASTROCYTE FORM FOLLOWS FUNCTION............................................... 3

1.4.................. SPECIES-SPECIFIC ASTROCYTE FORM MAY REVEAL SPECIALIZED FUNCTION............................................................................................................ 6

1.5.................. TOOLS TO REVEAL MORPHOLOGY AND INTERROGATE ASTROCYTE FUNCTION IN PRIMATES................................................................................ 8

1.6.................. PATHOPHYSIOLOGY OF PARKINSON’S DISEASE AND THE MPTP NON-HUMAN PRIMATE MODEL............................................................................................ 12

1.7.................. IMPORTANCE OF THE GPE IN PARKINSONISM.................................... 16

1.8.................. RELEVANCE OF THE ASTROCYTE NETWORK IN THE GPE IN PARKINSONISM............................................................................................................................... 18

1.9.................. FRAMEWORK FOR THE DISSERTATION................................................. 19

CHAPTER 2: Scaled complexity of mammalian astrocytes: insights from mouse and macaque        24

2.1.................. ABSTRACT......................................................................................................... 25

2.2.................. INTRODUCTION............................................................................................... 25

2.3.................. MATERIALS AND METHODS........................................................................ 27

2.4.................. RESULTS............................................................................................................. 39

2.5.................. DISCUSSION...................................................................................................... 46

2.6.................. LIMITATIONS................................................................................................... 50

CHAPTER 3: Exploring differences in astrocyte morphology and protein expression between normal and parkinsonian non-human primates............................................................ 65

3.1.................. ABSTRACT......................................................................................................... 66

3.2.................. INTRODUCTION............................................................................................... 67

3.3.................. MATERIALS AND METHODS........................................................................ 68

3.4.................. RESULTS............................................................................................................. 75

3.5.................. DISCUSSION...................................................................................................... 78

3.6.................. LIMITATIONS................................................................................................... 81

CHAPTER 4: Functional assessment of astrocytes in the globus pallidus of normal and parkinsonian non-human primates........................................................................................... 89

4.1.................. ABSTRACT......................................................................................................... 90

4.2.................. INTRODUCTION............................................................................................... 90

4.3.................. MATERIALS AND METHODS........................................................................ 92

4.4.................. RESULTS............................................................................................................. 99

4.5.................. DISCUSSION.................................................................................................... 102

4.6.................. LIMITATIONS................................................................................................. 104

CHAPTER 5: Discussion........................................................................................................... 112

5.1.................. SUMMARY OF RESULTS.............................................................................. 113

5.2.................. CRITICAL ASSESSMENT OF METHODOLOGY..................................... 115

5.3.................. FUTURE DIRECTIONS.................................................................................. 120

REFERENCES.......................................................................................................................... 122

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palavra-chave	primate parkinsonism astrocyte
Committee Chair / Thesis Advisor	Adriana Galvan, Emory University
Committee Members	Yoland Smith, Emory University Steven Sloan, Emory University Baljit Khakh, UCLA Ellen Hess, Emory University

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