Experimental and computational evidence for regulation of synaptic conductance via graded homeostasis of post-synaptic chloride concentration Öffentlichkeit
Archila, Santiago (2013)
Abstract
Neuronal networks often alter the strength of their synaptic connections in response to activity perturbations. The general understanding is that these responses exist to compensate for the perturbation and recover normal activity, though the dynamics of this synaptic plasticity, how it affects ongoing network activity, and how such regulation might be mediated are unclear. In this work, I aimed to answer these questions by monitoring the conductance dynamics of a single identified synapse - the inhibitory lateral pyloric (LP) to pyloric dilator (PD) synapse in the stomatogastric ganglion of the crab Cancer borealis - in response to a post-synaptic voltage perturbation. Though the voltage perturbation affected activity and triggered a change in synaptic conductance, I show that the synapse did not appear to influence any attribute of network activity. Instead, by matching the experimental results with those of a computational model, I found that the response was consistent with homeostatic regulation of post-synaptic internal chloride, the primary permeant ion through these synaptic channels. Finally, I show experimentally that direct disruption of chloride levels alone - by targeting an iontophoretic injection of chloride into PD without disrupting network activity - can trigger a change in synaptic conductance, uncovering experimental evidence consistent with a graded regulation of synaptic conductance driven by post-synaptic chloride homeostasis.
Table of Contents
Chapter 1 : General introduction........... 1
Stability from variable underlying parameters..... 2
Stability may be achieved through regulation mechanisms that target cell-intrinsic or synaptic properties..... 5
Homeostatic synaptic plasticity..... 9
Inhibitory homeostatic synaptic plasticity..... 10
Central pattern generators display highly stable network activity..... 12
The pyloric central pattern generator as a model system..... 13
The LP-to-PD pyloric synapse..... 19
Is electrical activity the true target of homeostatic synaptic plasticity?..... 24
Objectives of this dissertation..... 27
Chapter 2 : evidence for regulation of inhibitory synaptic conductance by post-synaptic chloride concentration homeostasis........... 29
Introduction....... 30
Results....... 35
Using model pyloric networks to investigate the network activity effects of changes to LP-to-PD synaptic strength..... 35
Post-synaptic voltage perturbation triggers change in LP-to-PD synaptic strength..... 44
Post-synaptic voltage perturbation affects pyloric network activity..... 53
Post-synaptic voltage perturbation affects synaptic reversal potential and synaptic currents..... 55
Analyzing the extent of homeostatic synaptic regulation among network attributes..... 58
Computational model of [Cl-]-dependent homeostatic synaptic regulation..... 72
Post-synaptic chloride injection triggers reduction in LP-to-PD synaptic strength..... 78
Discussion....... 86
Chapter 3 : Detailed methods........... 97
Network model database study..... 98
Experimental design..... 104
Dissection..... 102
Data acquisition and electrophysiology..... 106
Data analysis..... 115
Computational model of Cl--dependent homeostatic synaptic regulation..... 119
Chapter 4 : General Discussion........... 123
Overall summary..... 124
Chloride in STG neurons..... 126
Chloride in other neurons..... 128
Transduction of intracellular chloride signal..... 131
Is electrical activity the true target of homeostatic synaptic plasticity? (revisited)..... 132
Future directions..... 133
Final words..... 138
References........... 140
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