Dissertation/Thesis Abstract

All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability are Coregulated by Camkiv, While Inhibitory Synaptic Scaling is Under Independent Control
by Joseph, Annelise K., Ph.D., Brandeis University, 2017, 92; 10276021
Abstract (Summary)

Despite being comprised of networks with extensive positive feedback, the brain is able to prevent runaway activity. Neural networks are remarkably good at maintaining an activity setpoint while still permitting learning-related or developmental plasticity. To accomplish the delicate balance between change and stability, neural networks employ a group of homeostatic negative feedback mechanisms. This suite of homeostatic mechanisms sense and adjust neuronal excitability to keep firing rates within some target range. To date, the most well described manner in which neurons homeostatically regulate their excitability is through adjustment of excitatory or inhibitory synaptic weights, or by modulating their intrinsic excitability. It is perplexing why the neuron should have several means to accomplish the same outcome. Experiments demonstrating the collaborative or solo induction of homeostatic mechanisms have provided only limited insight into how homeostatic signaling pathways are organized to generate and maintain firing rate set-points (FRSP).

In order for neurons to maintain a FRSP, deviations from this value must modulate an internal signal that subsequently triggers homeostatic mechanisms to restore excitability to its set-point. The CaMKIV pathway is a calcium-dependent signaling element that plays a crucial role in regulating excitatory synaptic strength. The CaMKIV cascade is highly sensitive to activity and can modulate transcription, making it an ideal candidate to integrate incoming activity and modulate the excitability of neurons. Therefore, the major aim of this thesis was to characterize the role of CaMKIV in inducing multiple forms of homeostatic plasticity in tandem. Here we leverage our expertise in measuring homeostasis in neocortical neurons in vitro to determine how manipulating the activation state of nuclear CaMKIV affects neuronal excitability.

We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally induced by manipulating CaMKIV activity even without any perturbations to network activity. In contrast, CaMKIV had no impact on inhibitory synaptic weights. Additionally, we found that CaMKIV activity bidirectionally regulated spontaneous firing rates. Taken together, our data suggests that CaMKIV activity is used by the neuron to monitor the firing set point and gate homeostatic mechanisms to correct for drift from this target. The data presented in this thesis contribute that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, while inhibitory synaptic scaling is sensed and regulated through an independent signaling mechanism. This body of work contributes to a better understanding of neuronal homeostasis and will hopefully help us determine how malfunctions in homeostatic plasticity contributes to neurological and neurodevelopmental disorders.

Indexing (document details)
Advisor: Turrigiano, Gina G.
Commitee: Chen, Chinfei, Garrity, Paul, Nelson, Sacha, Paradis, Suzanne
School: Brandeis University
Department: Neuroscience
School Location: United States -- Massachusetts
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Biology, Molecular biology, Neurosciences
Keywords: Camkiv, Firing rate set-points, Homeostasis, Homeostatic signaling pathways, Intrinsic excitability, Synaptic scaling
Publication Number: 10276021
ISBN: 978-0-355-43555-9
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