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The role of the kinase activity of mitogen- and stress-activated kinase 1 in the environmental enrichment regulation of synaptic function, structure and hippocampal learning and memory
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Richardson, Philippa (2020) The role of the kinase activity of mitogen- and stress-activated kinase 1 in the environmental enrichment regulation of synaptic function, structure and hippocampal learning and memory. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3735711
Abstract
Environmental enrichment (EE) has a variety of positive cognitive effects and the mitogen- and stress-activated protein kinase 1 (MSK1) is in an optimal location for orchestrating translational changes in response to altered neuronal activity. It has been seen that the kinase function of MSK1 is necessary for regulating basal synaptic transmission strength, increasing mEPSCs amplitude after EE and for allowing cognitive flexibility. Changes in AMPA receptor (AMPAR) expression, particularly at the cell surface, is one possible explanation for MSK1- and EE- dependent effects on synaptic transmission.
In this thesis, I have compared wild-type mice and mice containing an inactive form of MSK1 (MSK1 KD), raised under either standard or EE conditions. After 3 months of EE, significant interactions between housing and genotype were identified in the AMPAR subunit GluA2, alongside two plasticity-related immediate early genes (IEGs), Arc and EGR1. This homeostatic regulation of IEG transcription corroborated what has previously been identified at the RNA level and these changes may reflect the alterations seen previously at the electrophysiological level. Using electron microscopy, I discovered that under basal conditions, the PSD length is shorter in MSK1 KD animals, suggestive of reduced protein accumulation at the post-synaptic membrane. I also performed behavioural studies and identified MSK1 KD animals to have significantly reduced exploratory behaviour and improved spatial working memory, which may reflect the underlying behavioural trait for the impairment in cognitive flexibility.
These studies provide new insights into the role that MSK1 plays in regulating key-plasticity related proteins and ultrastructural alterations and provides further clarity of the molecular pathways linking the long-lasting enrichmentinduced alterations underpinning cognitive and behavioural adaptations. Greater understanding of this pathway could provide new therapeutic avenues for patients with cognitive impairments.
| Item Type: | Thesis (PhD) | ||||
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| Subjects: | H Social Sciences > HV Social pathology. Social and public welfare Q Science > QL Zoology Q Science > QP Physiology |
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| Library of Congress Subject Headings (LCSH): | Environmental enrichment (Animal culture), Mice -- Environmental enrichment, Mitogen-activated protein kinases, Protein kinases, Neuroplasticity -- Molecular aspects, Cognition in animals -- Experiments, Cognition in animals -- Physiological aspects | ||||
| Official Date: | December 2020 | ||||
| Dates: |
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| Institution: | University of Warwick | ||||
| Theses Department: | School of Life Sciences | ||||
| Thesis Type: | PhD | ||||
| Publication Status: | Unpublished | ||||
| Supervisor(s)/Advisor: | Frenguelli, Bruno G. | ||||
| Sponsors: | University of Warwick. School of Life Sciences ; Biotechnology and Biological Sciences Research Council (Great Britain) | ||||
| Format of File: | |||||
| Extent: | 221 leaves : illustrations | ||||
| Language: | eng |
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