Molecular mechanisms of long-term Depression in the hippocampus

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology

Abstract

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, exerts its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus, and that they are involved in hippocampus-dependent learning and memory, it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. We and others have recently made molecular links between plasticity and disease, which suggests that dysregulation in synaptic plasticity may directly contribute to the aetiology of a number of neurological pathologies. For example, in the process of studying mechanisms of LTD in the hippocampus, we have recently identified key roles for a number of proteins that are linked to neuropathogies, including glycogen synthase kinase-3beta (GSK-3beta). We now plan to address several key unanswered questions concerning molecular mechanisms of NMDAR-LTD and mGluR-LTD in the hippocampus, with a focus on phosphorylation cascades, Ca2+ signalling and glutamate receptor trafficking. Based on extensive pilot data we plan to establish new components of molecular pathways underlying different forms of LTD, and to deduce precisely how induction of LTD, and the accompanying transient increase in cytosolic Ca2+, results in alterations in the synaptic expression of glutamate receptors. A key new development for our work will be the study of LTD in adult mice in vivo. We plan to establish how the signalling cascades that have been identified in simplified preparations operate in the intact animal. These findings will contribute to a fuller understanding of the molecular basis of major forms of synaptic plasticity in the brain, work that is directly relevant to a substantial number of major brain disorders

Technical Summary

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, has its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus and that they are involved in hippocampal-dependent learning and memory it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. For example, we have recently made molecular links between plasticity and disease, which suggests to us that dysregulation in synaptic plasticity may directly contribute to the aetiology of a condition. The purpose of this proposal is to understand how signalling pathways regulate synaptic plasticity in the hippocampus. We will investigate the roles of protein tyrosine kinases/phosphatases in the signalling mechanisms, Ca2+ signalling and how it relates to receptor trafficking . We shall also investigate how these signalling mechanisms relate to plasticity in vivo.

Planned Impact

Understanding how the brain works by regulating neuronal activity is a topic of great public and academic interest. Various forms of synaptic plasticity have been linked with many forms of learning and memory as well as other physiological functions, such as the perception of pain. Some of the strongest evidence linking plasticity to specific functions concerns the role of LTD in recognition memory and thus the work detailed in this proposal will appeal strongly, and be of use, to many interested parties. The target audiences are academics, pharmaceutical industry, health professionals, schools and the wider public.

ACADEMICS - The various ways neuroscientists, neuropharmacologists, neurologists, postdoctoral scientists employed on the project and the very wide range of undergraduate and postgraduate student benefit from this project are described under 'Academic beneficiaries'.

PHARMACEUTICAL INDUSTRY - Mutually beneficial collaborations with industry is an integral part of the way that we achieve our aims. GLC has worked as collaborator and consultant to a number of industrial companies for many years, including Eli Lilly, GlazoSmithKline, Merz and Merck. He has been a member of Lilly's Centre for Cognitive Neuroscience since its inception in 2008 and is in the process of setting up a new academic/industrial collaborative network, BrainCo, which will promote and accelerate pre-competitive neuroscience (detailed in the Pathways to Impact statement). Current industrial collaborations will be continue as at present and be expanded as conditions allow. The pharmaceutical industry is keen on such collaborations because it helps them with the identity and validation of new targets for their drug discovery programmes.

SCHOOLS - The future of science depends on enthusiastic young scientists. The applicants are involved in University open days, making explanation of science accessible to prospective students and parents while members of the research group are also involved in outreach programmes aimed at bringing the work of neuroscientists into schools and colleges. Researchers are also to be encouraged to undergo training to be confident about discussing sensitive issues, such as the use of animals in research, in schools to increase the understanding and awareness of young people. MA has already undertaken training with Understanding Animal Research.

THE WIDER PUBLIC - All applicants are committed to engage public interest and to shape public perception about the benefits of scientific discovery. We will take every opportunity to directly engage the public and schools through initiatives coordinated by the Bristol University Centre for Public Engagement, Bristol Neuroscience, MRC Centre for Synaptic Plasticity and by local attractions (e.g. the children's science activity centre '@Bristol'). Volunteering at Science festivals (such as British Association Summer Festival, Cheltenham Science Festival) is a very effective way of engaging the public in discussion about the value of science to society and such involvement will continue to be actively encouraged. Our published findings will be promoted to the public through Bristol Neuroscience and the University Press Office.

Publications

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Yoo J (2014) Shank mutant mice as an animal model of autism in Philosophical Transactions of the Royal Society B: Biological Sciences

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Kimura T (2014) Microtubule-associated protein tau is essential for long-term depression in the hippocampus in Philosophical Transactions of the Royal Society B: Biological Sciences

 
Title Glutamate receptor agonists and antagonists 
Description Selective agonists and antagonists have been generated by David Jane, a member of the MRC centre. This has been enhanced by the provision of new laboratory space that was funded in part by the MRC Centre grant. 
Type Of Material Improvements to research infrastructure 
Year Produced 2006 
Provided To Others? Yes  
Impact The compounds developed here are in use around the world in research and some are now commercially available through Accsent Scientific. 
 
Title Win LTP - software 
Description Software for the delivery of stimuli and e=analysis of electrophysiologigal data 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact adding to the research ability of labs across the world 
 
Description DT Monaghan 
Organisation University of Nebraska–Lincoln
Department University of Nebraska Medical Centre
Country United States 
Sector Academic/University 
PI Contribution Initial synthesis of novel compounds that act as NMDA receptor allosteric modulators. Analysis of effects on plasticty in in vitro slice preparations.
Collaborator Contribution Initial pharmacological characterisation of allosteric modulators using Xenopus Oocyte preparations.
Impact Publications in relevant journals
Start Year 2012
 
Description Eli Lilly 
Organisation Eli Lilly & Company Ltd
Country United Kingdom 
Sector Private 
PI Contribution Screening of cloned receptors for KAR antagonists
Collaborator Contribution screening of cloned receptors
Impact New antagonists developed, eg UBP296
 
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 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
 
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 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 activities about the brain and how memory works

Interst from school children
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description Understanding Animal Research 
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 Members of the Centre, including the Scientific Officer, have received training to prepare them for going to secondary schools to talk about the use of animals in biomedical research, in collaboration with Understanding Animal Research. A couple of PIs have been doing this for a short while.

While difficult to determine, a greater understanding of why animals are used in research and drug development is gained.
Year(s) Of Engagement Activity 2010,2011,2012,2014
 
Description public talks - various 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talks to public audiences on aspects of our work

interst in our work
Year(s) Of Engagement Activity 2006,2007,2008,2014