dc.contributor.author | Matos Pinto, Thiago | |
dc.date.accessioned | 2013-09-10T07:05:30Z | |
dc.date.available | 2013-09-10T07:05:30Z | |
dc.date.issued | 2013-09-03 | |
dc.identifier.uri | http://hdl.handle.net/2299/11560 | |
dc.description.abstract | Many molecules and the complex interactions between them underlie plasticity in
the cerebellum. However, the exact relationship between cerebellar plasticity and
the different signalling cascades remains unclear. Calcium-calmodulin dependent
protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but very
little is known about its function during plasticity induction in the cerebellum.
The aim of this thesis is to contribute to a better understanding of the molecular
mechanisms that regulate the induction of synaptic plasticity in cerebellar Purkinje
cells (PCs). The focus of the thesis is to investigate the role of CaMKII isoforms
in the bidirectional modulation of plasticity induction at parallel fibre (PF)-PC
synapses. For this investigation, computational models that represent the CaMKII
activation and the signalling network that mediates plasticity induction at these
synapses were constructed.
The model of CaMKII activation by calcium-calmodulin developed by Dupont et
al (2003) replicates the experiments by De Koninck and Schulman (1998). Both theoretical
and experimental studies have argued that the phosphorylation and activation
of CaMKII depends on the frequency of calcium oscillations. Using a simplified
version of the Dupont model, it was demonstrated that the CaMKII phosphorylation
is mostly determined by the average calcium-calmodulin concentration, and
therefore depends only indirectly on the actual frequency of calcium oscillations. I
have shown that a pulsed application of calcium-calmodulin is, in fact, not required
at all. These findings strongly indicate that the activation of CaMKII depends on
the average calcium-calmodulin concentration and not on the oscillation frequency
per se as asserted in those studies.
This thesis also presents the first model of AMPA receptor phosphorylation
that simulates the induction of long-term depression (LTD) and potentiation (LTP)
at the PF-PC synapse. The results of computer simulations of a simple mathematical
model suggest that the balance of CaMKII-mediated phosphorylation and
protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors determines
whether LTD or LTP occurs in cerebellar PCs. This model replicates the
experimental observations by Van Woerden et al (2009) that indicate that CaMKII
controls the direction of plasticity at PF-PC synapses. My computer simulations
support Van Woerden et al’s original suggestion that filamentous actin binding can
enable CaMKII to regulate bidirectional plasticity at these synapses.
The computational models of intracellular signalling constructed in this thesis
advance the understanding of the mechanisms of synaptic plasticity induction in
the cerebellum. These simple models are significant tools for future research by the
scientific community. | en_US |
dc.language.iso | en | en_US |
dc.publisher | University of Hertfordshire | en_US |
dc.rights | info:eu-repo/semantics/openAccess | en_US |
dc.subject | CaMKII | en_US |
dc.subject | calcium | en_US |
dc.subject | calmodulin | en_US |
dc.subject | learning | en_US |
dc.subject | memory | en_US |
dc.subject | long-term depression | en_US |
dc.subject | long-term potentiation | en_US |
dc.subject | cerebellum | en_US |
dc.subject | signalling pathways | en_US |
dc.subject | signal transduction | en_US |
dc.subject | simulation | en_US |
dc.subject | computational neuroscience | en_US |
dc.title | Computational Models of Intracellular Signalling and Synaptic Plasticity Induction in the Cerebellum | en_US |
dc.type | info:eu-repo/semantics/doctoralThesis | en_US |
dc.identifier.doi | 10.18745/th.11560 | |
dc.identifier.doi | 10.18745/th.11560 | |
dc.type.qualificationlevel | Doctoral | en_US |
dc.type.qualificationname | PhD | en_US |
herts.preservation.rarelyaccessed | true | |