Mechanisms of NMDA receptor-dependent LTP and LTD in the hippocampus.

Lead Research Organisation: University of Bristol
Department Name: Anatomy

Abstract

The human brain contains an enormous network of neurons which communicate via specialised connections known as synapses. Synapses are fundamental to brain function but they are not permanently fixed, instead synapses are made and lost throughout life in response to changes in brain activity. In addition, the strength of a synapse can be modified to make the connection between neurons more or less effective. This process, known as synaptic plasticity, enables the activity of neuronal networks to be altered by experience. Synaptic plasticity is therefore believed to underlie our ability to learn and remember. The mechanisms of synaptic plasticity have been extensively studied in rodent hippocampus, a brain region essential for memory formation. The proposed research will investigate one form of synaptic plasticity, long-term potentiation, in rat hippocampal neurons. We will investigate the changes that occur to strengthen synapses during long-term potentiation, and how these changes actually happen. The results will increase our understanding of how changes in synaptic plasticity relate to changes in neuronal function and learning processes.

Technical Summary

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission. There are two main long-lasting forms of synaptic plasticity termed long-term potentiation (LTP) and long-term depression (LTD). Most forms of LTP, and many forms of LTD, are triggered by the synaptic activation of NMDA receptors (NMDARs) and subsequently involve alterations in the efficiency of transmission mediated by AMPA receptors (AMPARs). While significant progress has been made in understanding synaptic plasticity, there are still large gaps in our knowledge, particularly the mechanisms by which activation of NMDARs leads to alterations in the functioning of AMPARs. In the current proposal we will utilise an integrated multidisciplinary approach, which will combine extracellular and whole-cell recording, two-photon confocal imaging and uncaging experiments, pharmacology, biochemistry & molecular biology and neuronal modelling. By using rat hippocampal brain slices and cultures we shall investigate four main areas. We shall build on our previous work characterising developmental alterations in the expression mechanisms of LTP, which showed that changes in probability of glutamate release, AMPAR single channel conductance, and AMPAR number are involved in LTP expression at different ages. Importantly in this section we shall investigate LTP expression mechanisms in adult animals, which have been largely ignored until now. We shall determine how AMPAR number and subunit composition at the cell surface is controlled during LTP and LTD. By studying proteins that interact with AMPARs and are important for their trafficking and surface expression we aim to identify the precise role of these proteins in synaptic plasticity. In addition, we will make use of fluorescently tagged AMPAR subunits to monitor their surface expression and real time movement into and out of synapses during synaptic plasticity. Finally, we will examine the signalling cascades, in particular the role of protein kinases and phosphatases, which regulate these protein interactions and thus AMPAR trafficking. These studies will address several outstanding issues of LTP and LTD.

Publications

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Bortolotto ZA (2011) Synaptic plasticity in the hippocampal slice preparation. in Current protocols in neuroscience

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Bradley CA (2012) A pivotal role of GSK-3 in synaptic plasticity. in Frontiers in molecular neuroscience

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Clarke VR (2012) Synaptic kainate receptors in CA1 interneurons gate the threshold of theta-frequency-induced long-term potentiation. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description BBSRC Project Grant
Amount £508,297 (GBP)
Funding ID BB/K019899/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 08/2016
 
Description BBSRC Research Grant
Amount £560,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2009 
End 08/2012
 
Description Europena Research Council FP7
Amount € 2,500,000 (EUR)
Funding ID 341089 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 02/2014 
End 01/2019
 
Description WT/MRC Neurodegeneration initiative
Amount £9,200,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 02/2015
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution CASE studentship to investigate ....
Collaborator Contribution CASE studentship award
Impact publications..
Start Year 2008
 
Description Lilly 
Organisation Eli Lilly & Company Ltd
Country United Kingdom 
Sector Private 
PI Contribution provided experimental data on gluatamate receptor clonal cell lines
Collaborator Contribution experimental data on gluatamate receptor clonal cell lines
Impact publications ...
 
Description NIH 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution provision of experimental data
Collaborator Contribution provision of experimantal data
Impact publications ...
Start Year 2007
 
Description Seoul National University 
Organisation Seoul National University
Department Brain & Cognitive Sciences
Country Korea, Republic of 
Sector Academic/University 
PI Contribution Expertise in electrophysiological investigations of LTP/LTD.
Collaborator Contribution Collaboration on electrophysiological investigation sof LTP/LTD in pain pathways. Expertise and facilities for multiphoton microscopy
Impact a number of papers in high impact journals (Science, Neuron)
Start Year 2010
 
Description TY Wang 
Organisation University of British Columbia
Country Canada 
Sector Academic/University 
PI Contribution Provision of principal experimental data
Collaborator Contribution Provision of experimental data
Impact publications
Start Year 2006
 
Description Yale 
Organisation Yale University
Country United States 
Sector Academic/University 
PI Contribution provision of experimental data
Collaborator Contribution provision of experimental data
Impact publications ...
Start Year 2008
 
Title Update to Win-LTP software 
Description An update to the Win-LTP software developed in the previous grant (G9532377) 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2008
Licensed No
Impact in use in many labs across the world
 
Title WinLTP 
Description Software to perform electrophysiological experiments 
Type Of Technology Software 
Year Produced 2006 
Impact This software is currently in use in a range of laboratories throughout the world 
 
Description BAAS meeting, Liverpool 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact talk to public audience on music and memory at the BAAS meeting at Liverpool, looking at the role of plasticity in memory

good response and interest from the public
Year(s) Of Engagement Activity 2008
 
Description Bristol Neuroscience Festival 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact over 200 people attended the talk, which was very well received

audience conformed interest
Year(s) Of Engagement Activity 2013
 
Description MRC Pop Up Festival of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact over 100 attendees for the talk(s) followed by engagement activities

the talk was well received. Engagement activities with the general public sparked much interest and fun!
Year(s) Of Engagement Activity 2013
 
Description School visits - various 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact talks and hands-on activities to school students.

interest and good feedback from the children
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description Web Site 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Writing material for departmental and MRC Centre web sites

good feedback from audience;
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012