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

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

Abstract

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.

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M01116X/1 01/10/2015 30/09/2023
1643072 Studentship BB/M01116X/1 05/10/2015 30/09/2019 Daniel David Cooper
 
Description This project focused on the effects of environmental enrichment, a housing condition for mice that features increased cognitive, social and visual stimulation compared to standard housing conditions. Environmental enrichment is thought to parallel humans who have experienced increased cognitive stimulation (such as those possessing tertiary education qualifications) and increased levels of exercise, both of which stimulate neuroplasticity and have neuroprotective effects. A key target of environmental enrichment within the brain, the hippocampus, plays a key role in spatial and social memory acquisition and consolidation. This has previously been determined by experimental hippocampal lesions in model organisms and correlative studies with humans.

Over the course of this project a key molecular mechanism, thought to underlie some of the effects of environmental enrichment, was investigated in order to better understand how experience can cause changes within the hippocampus. MSK1, a protein kinase that is activated by external cell signals such as BDNF (a key molecule in mediating the effects of environmental enrichment), was the focus of this investigation. The ability of MSK1, once activated, to change other proteins (through its kinase activity) was thought to be important to the changes in the hippocampus mediated by environmental enrichment. This was investigated within "CA1" cells of the hippocampus, cells that play a key role in encoding sensory information to generate cognitive maps of the environment.

During the course of this award, a few key findings were made:

1) Previous publications implicate the activity-dependent upregulation of BDNF in modulating some of the hippocampal effects of environmental enrichment. CREB is an intracellular transcription factor which is important for neuroplasticity changes within neurons. Observing the kinase activity of MSK1 linking extracellular BDNF signalling to intracellular CREB activation strengthened evidence for MSK1 kinase activity as a mechanistic link between BDNF release and neuroplasticity changes. This work was published in the paper Daumas et al. (2017) which is included in this report.

2) Transcriptomic investigation was conducted to establish the effect of enrichment on gene expression. Activation of CREB, a transcription factor regulated by MSK1, was hypothesised to underlie the effects of environmental enrichment through the regulation of gene expression. A substantial role was found for the kinase activity of MSK1 in regulating the transcriptomic response induced by 3 months of environmental enrichment. This work was also important due to the length of enrichment utilised: The majority of published environmental enrichment studies utilise timepoints ranging from 1-8 weeks, with few assessing longer time points, and even fewer employing the depth of sequencing used here. This work has been submitted for publication and is currently under review.

3) A new role for MSK1 kinase activity in regulating behaviour was observed. This behaviour has not been previously studied in the context of MSK1 kinase inactivation, and indicates that MSK1 plays a role in behaviours outside of spatial memory. This highlights the potential importance MSK1 in new fields of study, and gives greater context to the signalling pathways introduced above.
Exploitation Route Understanding how the environment plays a role in the remodelling of the brain, and can contribute to a brain better equipped to tackle challenges is important for understanding learning and memory and for developing ways to alleviate a lack of cognitive enrichment, either environmentally, or pharmacologically. Currently, the molecular mechanisms underlying the benefits of environmental enrichment are unclear. This work highlights several key differences in gene expression between enriched and non-enriched animals that are under the control of the kinase activity of MSK1, and may underlie the beneficial effects of enrichment reported throughout the literature. These genes could form novel targets of investigation, either as markers for improved cognition, or as pharmacological targets for nootropics (cognition enhancing drugs). Of note, a nootropic was also tested in this work on acute hippocampal slice preparations and appeared to work, in a similar MSK1-dependent manner, to BDNF (an endogenous neuropeptide important in learning and memory). The kinase activity of MSK1 itself has been demonstrated to be important for enrichment-mediated changes in gene expression, glutamate receptor subunit composition, social memory and synaptic changes within the hippocampus, further clarifying the mechanistic underpinnings of environmental enrichment.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Neuroscience outreach event (University of Warwick) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Nearly 100 members of the general public attended a neuroscience outreach evening at Warwick university, lead by Prof. Nicholas Dale. Attendees were invited to participate in practical workshops demonstrating various neurological phenomena before listening to seminars given by senior academics showcasing the real-world impact that neuroscience research at Warwick is having. The event was held to try to capture public interest and provide an opportunity for local residents and those affiliated with the university to learn more about our activities here. Public feedback was very positive, with many remarking that they came away more interested and informed about neurobiology in general.
Year(s) Of Engagement Activity 2016
 
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 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