Mathematical modelling of synaptic tagging and capture mechanisms to investigate morphological changes during synaptic plasticity : A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy at Lincoln University
The synaptic tagging and capture (STC) hypothesis not only explains the integration and association of synaptic activities, but also the formation of learning and memory. The synaptic pathways involve in the synaptic tagging and capture phenomenon are called STC pathways. It is challenging to associate the physical attributes of STC pathways with structural changes along with synaptic strength. Mathematical modelling and computational analysis provide a way to explain the complexity of STC mechanisms along with their structural impact on a single dendritic spine. In this study, we develop mathematical models based on significant reported networks involved in synaptic tagging. We use this model to explore events associated with synaptic tagging candidates and evaluate them against the assumption based on STC hypothesis. Our model explains the integrated activities of kinases (CaMKII, PKA, MAPK/ERK) in response to the initial stimulation and setting of tags, the effect of this on overall synaptic tag strength, and the induction of L-LTP with protein synthesis. We use this model to investigate the behaviour of different published synaptic tagging candidates and examine it against the criteria laid out in the synaptic tagging hypothesis. Our model reveals that CaMKII activation (Tag1) is critical for the setting of the initial tag; however, coordinated activity with other kinases and the biochemical pathway is necessary for the tag to be stable. Similarly, PKA modulates NMDAR-mediated Ca2+ signalling. PKA and CaMKII likely act in concert in the process of tagging. We extend our model to investigate structural aspects of synaptic plasticity; we add the effects of actin remodelling and AMPARs anchoring on spine dynamics. The Spine model verifies that AMPARs are anchored in the PSD via scaffolding proteins and cytoskeletal elements to ensure reliable synaptic transmission. We introduce critical variables in the Extended-spine model to analyse the contribution of significant events leading to dendritic spine structural change. Our model associates the physical and structural aspects of synaptic plasticity link with spine dynamics. We find that a simple activation-inhibition loop can be used as paradoxical signalling to investigate the dynamics of kinases like CaMKII, the RhoGTPases-Rho and Cdc42, and actin remodelling. Hence, the interface between actin barbed end generation and signalling is a source of natural robustness, regardless of model sensitivity to kinetic parameters.... [Show full abstract]
Keywordssynaptic tagging and capture; synaptic plasticity; CaMKII; Calmodulin; dendritic spines; Ca2+; actin remodelling; NMDAR; AMPAR; synaptic transmission; PKA; mathematical modelling; parameter estimation; ordinary differential equations; kinetic modelling; signalling hypothesis
Fields of Research3102 Bioinformatics and computational biology; 310208 Translational and applied bioinformatics; 460102 Applications in health
Access RightsRestricted item. Embargoed until 13 July 2024
Showing items related by title, author, creator and subject.
He, Yao (Lincoln University, 2015)Synaptic plasticity, an emergent property of the synaptic networks, has shown strong correlation to one of the essential functions of the brain, memory formation. Through understanding synaptic plasticity, we may discover ...
A mathematical model of synaptotagmin 7 revealing functional importance of short-term synaptic plasticity He, Yao; Kulasiri, Gamalathge D.; Liang, Jingyi (Medknow Publications, 2019-04)Synaptotagmin 7 (Syt7), a presynaptic calcium sensor, has a significant role in the facilitation in short-term synaptic plasticity: Syt7 knock-out mice show a significant reduction in the facilitation. The functional ...
Increased zinc and manganese in parallel with neurodegeneration, synaptic protein changes and activation of Akt/GSK3 signaling in ovine CLN6 neuronal ceroid lipofuscinosis Kanninen, K. M.; Grubman, A.; Meyerowitz, J.; Duncan, C.; Tan, J.-L.; Parker, S. J.; Crouch, P. J.; Paterson, B. M.; Hickey, J. L.; Donnelly, P. S.; Volitakis, I.; Tammen, I.; Palmer, David N.; White, A. R. (Public Library of Science, 2013-03-14)Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis (NCL; Batten disease). CLN6 loss leads to disease clinically characterized by vision impairment, motor and cognitive dysfunction, ...