SSA: Determining the role of MSK1 in synaptic plasticity and enrichment

Persistent alterations to neuronal structure and function underpins behavioural and cognitive changes that occur in response to experiences. These changes can occur at the level of gene expression, inducing a different proteome within neurons, allowing long-term changes to neuronal function. Understanding the intracellular mechanisms of synaptic plasticity will provide greater understanding of learning and memory and may provide new targets for therapy against neurodegenerative diseases conditions such as Alzheimer's disease.
Mitogen-and stress-activated kinase 1 (MSK1) is a key regulator of gene expression. MSK1 can be activated by brain-derived neurotrophic factor (BDNF) which appears to increase during enriched experiences in micerodents. Social and sensory enrichment for mice is introduced by having larger numbers of cage mates, exercise wheels and toys, ladders and tunnelstubes within their environment. After MSK1 is activated by BDNF it can phosphorylate cAMP response element binding protein (CREB). CREB has been shown to transduce neuronal activity and modify synaptic functions accordingly. To understand the role of MSK1, a kinase dead MSK1 (MSK1 KD) mutant was produced. In these MSK1 KD mice, neurons no longer downregulate activity-regulated cytoskeleton-associated protein/ activity regulated gene 3.1 (Arc/Arg3.1) which impacts AMPA receptorsAMPAR during homeostatic synaptic scaling. Reductions in Arc/Arg3.1 has shown increased AMPAR function and abolishes homeostatic scaling of AMPAR.
Direct evaluation of the impact that MSK1 has on localisation of glutamate receptor subunits such as GluA1 will help further understand the role of MSK1 on neuronal scaling and in response to enrichment. To do this, quantification and distribution of glutamate receptor subunits within CA1 of the hippocampus will be undertaken. This can include western blotting, biotinylation and immunohistochemistry studies. To further evaluate the localisation of glutamate receptor subunits immunogold electron microscopy will also be used.