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

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1786906 Studentship BB/M01116X/1 03/10/2016 31/12/2020 Philippa Loraine Richardson
 
Description Neuroscience seminar series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact I have reintroduced the Neuroscience seminar series at Warwick. This currently involves postgraduate students explaining their research for 20 minutes followed by questions. this leads to discussions about their work and hopefully fresh pairs of eyes for further study ideas.
Year(s) Of Engagement Activity 2018,2019
 
Description Open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact This was an open day visit for prospective undergraduate students. This was intended to demonstrate some of the research being undertaken in life sciences at Warwick University.
Year(s) Of Engagement Activity 2018
 
Description Public science evening 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An informative evening on aging and the brain and lifestyle changes that can be implemented to help with the effects of aging. I demonstrated with a microscope describing how neurons alter with aging.
Year(s) Of Engagement Activity 2018
 
Description School Visit (Coventry) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A visit to a local school to discuss careers in science
Year(s) Of Engagement Activity 2019
 
Description Science Gala 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Mainly primary school students but also some secondary school students came to find out more about STEM subjects and our stand was about neuroscience. Discussed different aspects of the brain and memory with students and parents and hopefully this sparked interest for the future.
Year(s) Of Engagement Activity 2019
URL https://warwick.ac.uk/fac/cross_fac/xmas/impact/xmas_scientist_experienceb/science_gala_2019/
 
Description Work experience in my lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Three students from a local WP school participated in a week of research-based activities, at the end of which they presented some of the work they had been exposed to
Year(s) Of Engagement Activity 2019