The GABAA receptor is a critical part of the sensingmachinery that triggers homeostatic plasticity of synaptic strengthand intrinsic excitability. Open Access
Wilhelm, Jennifer Caldwell (2008)
Abstract
Generating and maintaining stability is a problem that neural networks must manage during development. Whereas Hebbian forms of plasticity allow for fast experience-dependent modification of synapses, these changes in synaptic strength can lead to the destabilization of neuronal firing rates if long-term potentiation and long-term depression are unconstrained. A new set of mechanisms, termed homeostatic plasticity, aids in the stabilization of network spiking activity by restraining the average amount of spiking activity within a cell or a network of cells within a set range. Experimentally homeostatic plasticity has been examined by pushing spiking activity to extremes; either all activity is blocked or activity is highly enhanced. Studies in multiple experimental systems have found that chronically reducing spiking activity in synaptically connected neurons triggers coordinated increases in excitatory synaptic strength as well as increases in intrinsic cellular excitability. These changes are thought to be homeostatic as they act to increase activity to recover normal levels. The mechanisms by which cells monitor spiking activity and trigger compensatory changes in synaptic strength are not well understood. Cells could monitor the average level of membrane depolarization or the activation of neurotransmitter receptors as a proxy for activity. Few studies have been able to separate the roles of membrane depolarization and neurotransmission. However, using the developing chick embryonic spinal cord, we are able to block either excitatory GABAAergic or glutamatergic transmission without significantly altering membrane depolarization. We found that blocking GABAA receptors, but not glutamate receptors, triggered compensatory increases in synaptic strength and cellular excitability similar to those demonstrated after activity block. This suggests a special role for the GABAA receptor as a critical part of the machinery that senses changes in activity and triggers compensatory mechanisms.
Table of Contents
1 CHAPTER 1: GENERAL INTRODUCTION
3 Homeostatic regulation of neuronal firing rates
5 Homeostatic regulation of activity: scaling of quantal amplitudes
8 Homeostatic synaptic scaling: possible mechanisms
11 Homeostatic synaptic scaling: potential signaling molecules
14 Homeostatic regulation of activity: changes in mPSC frequency
16 Possible sensors for activity
18 Differences between homeostatic and Hebbian synaptic plasticity
20 Homeostatic plasticity: homeostatic changes in cellular excitability
22 Spontaneous network activity (SNA) in developing systems
25 SNA after neurotransmitter block in the in vitro chick spinal cord
27 SNA and homeostatic synaptic plasticity
28 Dissertation objectives
36 CHAPTER 2: GABAA TRANSMISSION IS A CRITICAL STEP IN THE PROCESS OF TRIGGERING HOMEOSTATIC INCREASES IN QUANTAL AMPLITUDE
37 ABSTRACT
38 INTRODUCTION
41 RESULTS
41 Activity block in ovo
41 Activity block increased SNA frequency in vitro
42 Activity block increased mPSC amplitude
46 Neurotransmitter block in ovo
47 Neurotransmitter block does not alter SNA frequency in vitro
48 No change in mPSCs following AMPA/NMDA receptor block
49 GABAA receptor block increased mPSC amplitude
51 12-hour GABAA block did not induce changes in mPSC amplitude
53 Activity block, but not GABAA receptor block, accelerates the recovery from post-episode depression.
55 DISCUSSION
56 Transiently reducing SNA does not increase mPSC amplitudes
58 Changes to mPSC amplitude following neurotransmitter block
60 Activity and neurotransmission regulate different aspects of homeostasis
61 Recovery of SNA in ovo is not due to changes in quantal amplitude
63 Concluding remarks
63 EXPERIMENTAL PROCEDURES
63 Dissection
64 Lidocaine infusion
64 Pharmacological blockade of synaptic transmission
65 Whole cell electrophysiology: voltage clamp
65 Extracellular and intracellular solutions
65 Identification and characterization of spontaneous postsynaptic currents
67 Statistics
68 REMAINING QUESTIONS AND FUTURE DIRECTIONS
91 CHAPTER 3: BLOCK OF GABAA RECEPTORS TRIGGERS HOMEOSTATIC RECOVERY OF SPONTANEOUS NETWORK ACTIVITY BY CHANGES IN CELLULAR EXCITABILITY
92 ABSTRACT
93 INTRODUCTION
95 RESULTS
95 GABAA receptor block increases intrinsic excitability
97 GABAA receptor block increases INa
99 GABAA receptor block does not alter ICa
99 GABAA receptor block decreases IA and IK(Ca)
101 GABAA receptor block differentially regulates ionic current densities
102 K+ current densities do not appear to co-regulate
103 DISCUSSION
104 Reduced GABAergic transmission and network excitability both trigger increased cellular excitability
106 Coordinated regulation of ion channels
107 GABAA receptor as a sensor for cellular excitability and synaptic strength
108 Homeostatic changes in cellular excitability, not synaptic strength, lead to recovery of activity
109 Recovery of SNA after glutamatergic block
110 Concluding remarks
111 EXPERIMENTAL PROCEDURES
111 Pharmacological blockade of activity and synaptic transmission
112 Dissection
112 Whole cell electrophysiology: current and voltage clamp
113 Extracellular and intracellular solutions
114 Chemicals and drugs
114 Statistics
116 REMAINING QUESTIONS AND FUTURE DIRECTIONS
132 CHAPTER 4: GENERAL DISCUSSION
134 Homeostatic regulation of cellular excitability and quantal amplitude
135 The GABAA receptor as a critical signal during development
136 Non-specific drug effects are unlikely to trigger homeostatic processes
137 Is the GABAA receptor a bidirectional sensor for changes in activity?
139 Potential signaling pathways initiated by GABAA receptor block
143 Other sensors are necessary for the homeostatic regulation of activity
145 Is neurotransmission part of the sensing machinery in mature neurons?
146 Concluding remarks
149 REFERENCES
FIGURES AND TABLES
1 CHAPTER 1: GENERAL INTRODUCTION
29 Figure 1.1 Isolated STG neurons can produce rhythmic bursting activity
30 Figure 1.2 Alterations to network activity produces bidirectional compensatory changes in quantal amplitude
32 Figure 1.3 Homeostatic synaptic plasticity: a closed feedback loop?
33 Figure 1.4 Activity dependent regulation of multiple factors that contribute to the scaling of quantal amplitudes.
34 Figure 1.5 GABAergic signaling is depolarizing in early development
35 Figure 1.6 Episodes of SNA in the in vitro chick spinal cord
36 CHAPTER 2: GABAA TRANSMISSION IS A CRITICAL STEP IN THE PROCESS OF TRIGGERING HOMEOSTATIC INCREASES IN QUANTAL AMPLITUDE
73 Figure 2.1 Activity block in ovo
74 Figure 2.2 Activity block increases SNA frequency in vitro
75 Figure 2.3 Activity block increases GABA- and AMPA-mPSCs
79 Figure 2.4 Neurotransmitter block in ovo
80 Figure 2.5 Neurotransmitter block does not alter SNA frequency in vitro
81 Figure 2.6 Glutamate receptor block does not alter mPSCs
82 Figure 2.7 GABAA receptor block increases mPSCs
84 Figure 2.8 12 hours of GABAA receptor block does not alter mPSCs
85 Figure 2.9 Activity block, but not GABAA receptor block, accelerates recovery from post-episode depression
87 Figure 2.10 Schematic of experimental procedure
89 Figure 2.11 Identification of populations of mPSCs in motoneurons
90 Figure 2.12 mPSCs can be identified by decay kinetics
77 Table 2.1 mPSC properties: amplitude, frequency, and kinetics
78 Table 2.2 Passive membrane properties
88 Table 2.3 Acute TTX does not alter PSC properties
91 CHAPTER 3: BLOCK OF GABAA RECEPTORS TRIGGERS HOMEOSTATIC RECOVERY OF SPONTANEOUS NETWORK ACTIVTY THROUGH COMPENSATORY CHANGES IN CELLULAR EXCITABILITY
118 Figure 3.1 GABAA receptor block decreased spike threshold
121 Figure 3.2 INa is increased by GABAA receptor block
122 Figure 3.3 ICa is not altered by GABAA receptor block
123 Figure 3.4 IA is decreased by GABAA receptor block
125 Figure 3.5 IK(Ca) is decreased by GABAA receptor block
127 Figure 3.6 Current densities are differentially regulated
128 Figure 3.7 IA and IK(Ca) do not co-regulate
129 Figure 3.8. Activity recovery occur via increased cellular excitability
131 Figure 3.9 GABAA receptor and activity block trigger similar changes
120 Table 3.1 Membrane properties of motoneurons
132 CHAPTER 4: GENERAL DISCUSSION
149 REFERENCES
About this Dissertation
| School | |
|---|---|
| Department | |
| Subfield / Discipline | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Keyword | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
The GABAA receptor is a critical part of the sensingmachinery that triggers homeostatic plasticity of synaptic strengthand intrinsic excitability. () | 2018-08-28 15:28:56 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|