Quantitative Models of Calcium-Dependent Protein Signaling in Neuronal Dendritic Spines

Description

<p><a> Worldwide, as many as 1 billion people
suffer from neurological disorders. Fundamentally, neurological
disorders are caused by dysregulation of biochemical signaling within neurons,
leading to deficits in learning and memory formation. To identify better
preventative and therapeutic strategies for patients of neurological disorders,
we require a better understanding of how biochemical signaling is regulated
within neurons.</a></p>

<p> Biochemical
signaling at the connections between neurons, called synapses, regulates
dynamic shifts in a synapse’s size and connective strength. Called synaptic
plasticity, these shifts are initiated by calcium ion (Ca²⁺) flux into
message-receiving structures called dendritic spines. Within dendritic spines,
Ca²⁺ binds sensor proteins such as calmodulin (CaM). Importantly, Ca²⁺/CaM
may bind and activate a wide variety of proteins, which subsequently facilitate
signaling pathways regulating the dendritic spine’s size and connective
strength. </p>

<p>In this thesis, I use
computational models to characterize molecular mechanisms regulating Ca²⁺-dependent
protein signaling within the dendritic spine. Specifically, I explore how Ca²⁺/CaM
differentially activates binding partners and how these binding partners
transduce signals downstream. For this, I present deterministic models of Ca²⁺,
CaM, and CaM-dependent proteins, and in analyzing model output I demonstrate
in-part that competition for CaM-binding alone may be sufficient to set the Ca²⁺
frequency-dependence of protein activation. Subsequently, I adapt my
deterministic models into particle-based, spatial-stochastic frameworks to
quantify how spatial effects influence model output, showing evidence that
spatial gradients of Ca²⁺/CaM may set spatial gradients of activated
proteins downstream. Additionally, I incorporate into my models the most detailed
model to-date of Ca²⁺/CaM-dependent protein kinase II (CaMKII), a
multi-subunit protein essential to synaptic plasticity. With this detailed
model of CaMKII, my analysis suggests that the many subunits of CaMKII provide
avidity effects that significantly increase the protein’s effective affinity
for binding partners, particularly Ca²⁺/CaM. Altogether, this thesis
provides a detailed analysis of Ca²⁺-dependent signaling within
dendritic spines, characterizing molecular mechanisms that may be useful for
the development of novel therapeutics for patients of neurological disorders. </p>

Links & Downloads

1. 10.25394/pgs.8285963.v1

Tags

Protein Signaling

Neuroscience

Computational Biology

Additional Fields

Identifer	oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8285963
Date	15 August 2019
Creators	Matthew C Pharris (6848951)
Source Sets	Purdue University
Detected Language	English
Type	Text, Thesis
Rights	CC BY 4.0
Relation	https://figshare.com/articles/Quantitative_Models_of_Calcium-Dependent_Protein_Signaling_in_Neuronal_Dendritic_Spines/8285963