SSA - The Molecular Mechanisms of Experience-Dependent Synaptic Plasticity at both the Cellular and Behavioural Level.

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Learning and memory are fundamental processes that define an individual's identity, thoughts and personality. This project aims to characterise and understand fundamental molecular mechanisms of learning and memory mediated by the CREB activating kinase MSK1, providing insight into the molecular changes underlying synaptic plasticity. Greater activation of the synapse, and thus CREB phosphorylation up-regulates CREB-mediated gene transcription, eventually strengthening the synapse, and this change is associated with long-term memory formation.Over the course of this project, correlates of long-term memory formation will be looked at, such as neuron morphology, dendrite spine density and branching, the ion conductance properties of neurons, the localisation of proteins within the post-synaptic membrane, glutamate receptor subunit composition, RNA-sequencing data and spatial memory based behavioural assays in order to elucidate the molecular differences between the MSK1 kinase-dead (KD) mutant and the wildtype (WT) genotype brought about when each is raised in an enriched environment (a housing environment that has been previously observed to increase hippocampal spine density, and aid in spatial learning). Any differences detected would offer an insight into the molecular changes induced by MSK1 during memory formation.Previously generated MSK1 KD mice will be used, that are homozygous for a single point mutation in the MSK1 gene, disrupting the kinase activity of MSK1 specifically. Observations with the KD mutant mice indicate impaired spatial learning and a lack of response to environmental enrichment (less dense hippocampal dendritic trees) as compared to WT mice, indicating that the benefits of environmental enrichment are mediated at least in part by MSK1 kinase activity.Observation of differences in synaptic transmission and properties across genotypes and housing conditions will give an insight into the molecular mechanisms of learning and memory.