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.
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
Whitehead G
(2013)
Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.
in Brain : a journal of neurology
Lodge D
(2013)
Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors.
in Neuropharmacology
Collingridge GL
(2017)
Antidepressant Actions of Ketamine Versus Hydroxynorketamine.
in Biological psychiatry
Kang SJ
(2015)
Bidirectional modulation of hyperalgesia via the specific control of excitatory and inhibitory neuronal activity in the ACC.
in Molecular brain
Park P
(2016)
Calcium-Permeable AMPA Receptors Mediate the Induction of the Protein Kinase A-Dependent Component of Long-Term Potentiation in the Hippocampus.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Cao F
(2017)
Developmental regulation of hippocampal long-term depression by cofilin-mediated actin reorganization.
in Neuropharmacology
Tidball P
(2017)
Differential ability of the dorsal and ventral rat hippocampus to exhibit group I metabotropic glutamate receptor-dependent synaptic and intrinsic plasticity.
in Brain and neuroscience advances
France G
(2022)
Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators.
in Neuropharmacology
Choi JH
(2014)
Effects of PI3K? overexpression in the hippocampus on synaptic plasticity and spatial learning.
in Molecular brain
Kang H
(2017)
Ephenidine: A new psychoactive agent with ketamine-like NMDA receptor antagonist properties.
in Neuropharmacology
Amici M
(2021)
GSK-3ß regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIa.
in The European journal of neuroscience
Sanderson T
(2016)
Hippocampal metabotropic glutamate receptor long-term depression in health and disease: focus on mitogen-activated protein kinase pathways
in Journal of Neurochemistry
Whitcomb DJ
(2015)
Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus.
in Scientific reports
Volianskis A
(2015)
Long-term potentiation and the role of N-methyl-D-aspartate receptors.
in Brain research
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
France G
(2017)
Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus.
in Neuropharmacology
Park P
(2014)
NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Wallach J
(2016)
Pharmacological Investigations of the Dissociative 'Legal Highs' Diphenidine, Methoxphenidine and Analogues
in PLOS ONE
Tata BK
(2017)
Rabconnectin-3a is required for the morphological maturation of GnRH neurons and kisspeptin responsiveness.
in Scientific reports
Ng A
(2014)
Rapid regulation of endoplasmic reticulum dynamics in dendritic spines by NMDA receptor activation
in Molecular Brain
Ko HG
(2018)
Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury.
in Cell reports
Yoo J
(2014)
Shank mutant mice as an animal model of autism.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Collingridge GL
(2014)
Strippers reveal their depressing secrets: removing AMPA receptors.
in Neuron
Bliss TV
(2016)
Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain.
in Nature reviews. Neuroscience
Peineau S
(2018)
Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer's disease.
in Pharmacological research
Nisticò R
(2017)
Synaptoimmunology - roles in health and disease.
in Molecular brain
Lodge D
(2019)
The 1980s: D-AP5, LTP and a Decade of NMDA Receptor Discoveries.
in Neurochemical research
Sanderson TM
(2018)
The Probability of Neurotransmitter Release Governs AMPA Receptor Trafficking via Activity-Dependent Regulation of mGluR1 Surface Expression.
in Cell reports
Hoeller AA
(2016)
The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation.
in PloS one
De Bundel D
(2015)
Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
| 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 | 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015 |
| 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 |