The effects of acute stress on glutamate receptor trafficking and synaptic plasticity in the hippocampus
Lead Research Organisation:
University of Bristol
Department Name: Henry Wellcome LINE
Abstract
The ability of an animal to adapt to a changing environment is critically important for its survival. A very important aspect of this is the ability of the central nervous system to respond to periods of stress. During the initial acute response to a stressor the animal needs heightened vigilance and the ability to focus its attention, energy and cognitive functions on interpreting and responding to the perceived danger. Following this acute response phase the animal needs to tune down its aroused state and store appropriate memories of the event for future reference should similar dangers recur. If the animal continues to be subjected to repeated or prolonged stresses - particularly if they have been unpredictable and the animal has little or no ability to control or avoid them - the stress responses become maladaptive and result in loss of cognitive function and is associated with both physical and psychological disorders. In this application we intend to investigate the changes in synaptic function that occur during the early phase of the acute stress response / the time of heightened vigilance.
Technical Summary
It is of great evolutionary advantage for animals to adapt rapidly to a changing and challenging environment, and in particular for an animal to have a stress-responsive neuroendocrine system that can focus the animal's vigilance and strengthen the ability to remember critical information related to the stressful event. Whereas the effects of acute stress are of clear adaptive value to the animal, the cellular effects of chronic stress appear to be maladaptive with negative effects on mood and cognition both in rodents and man. In this application we intend to investigate the changes in synaptic function that occur during the early phase of the acute stress response. In particular we shall be looking at alterations in synaptic transmission and synaptic plasticity (long-term potentiation and long-term depression) in the hippocampus. We will investigate molecular mechanisms that regulate the function of AMPARs and NMDARs in these processes and how these are altered both by the acute application of corticosterone in vitro, and ex-vivo following exposure of a rat to an acute stressor.
Publications
Romberg C
(2012)
False recognition in a mouse model of Alzheimer's disease: rescue with sensory restriction and memantine.
in Brain : a journal of neurology
Bradley CA
(2012)
A pivotal role of GSK-3 in synaptic plasticity.
in Frontiers in molecular neuroscience
Jo J
(2010)
Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95.
in Nature neuroscience
Jang S
(2016)
Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity.
in Nature neuroscience
Jo J
(2011)
Aß1-42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3ß
in Nature Neuroscience
Nicolas CS
(2012)
The Jak/STAT pathway is involved in synaptic plasticity.
in Neuron
Yi JH
(2017)
Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus.
in Pharmacological research
Kailainathan S
(2016)
Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF).
in Pharmacological research
Kimura T
(2014)
Microtubule-associated protein tau is essential for long-term depression in the hippocampus.
in Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Description | In this proposal we plan to focus our studies on the changes that occur within the first four hours of exposure to acute stress or the application of exogenous glucocorticoids. In particular, we shall investigate NMDAR (N-methyl-D-aspartate receptor)-dependent forms of long-term potentiation (LTP) and long-term depression (LTD) at CA1 synapses in hippocampal slices and test the general hypothesis that stress causes changes in the trafficking of AMPARs (a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors) and NMDARs, which in turn leads to alterations in synaptic plasticity. |
Exploitation Route | It wold be important to develop further how this stress mediated CP-AMPA receptors regulate synaptic function by long-term stress. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | MRC-KHIDI signed MOU |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Description | Bristol-BSI RIKEN |
Organisation | RIKEN |
Department | RIKEN Brain Science Institute |
Country | Japan |
Sector | Public |
PI Contribution | Electrophysiological and molecular assays in vitro. |
Collaborator Contribution | Tau protein constructs and vivo electrophysiology |
Impact | Kimura K., Whitcomb D.J., Jo J., Regan R., Piers T., Heo S., Brown C., Hashikawa T., Murayama M., Seok H., Sotiropoulos I., Kim E., Collingridge G.L., Takashima A. and Cho K. (2013) Microtubule associated protein tau (MAPT) is essential for long-term depression in the hippocampus. Phil. Trans. R. Soc. B 369, 2013144. |
Start Year | 2012 |
Description | Bristol-Chonnam Univ Hospital |
Organisation | Chonnam National University Hospital (CNUH) |
Country | Korea, Republic of |
Sector | Hospitals |
PI Contribution | Set research lab in Chonnam Nat Univ Hospital. |
Collaborator Contribution | Molecular biology |
Impact | Whitehead G., Jo J., Hogg E.L., Piers T.M., Kim D.H., Seaton G., Seok H., Bru-Mercier G., Son G.H., Regan P., Hildebrandt L., Waite E., Kim B.C., Kerrigan T.L., Kim K., Whitcomb D.J., Collingridge G.L., Lightman S.L., Cho K. (2013). Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus. Brain 136, 3753-3765. Kimura K., Whitcomb D.J., Jo J., Regan R., Piers T., Heo S., Brown C., Hashikawa T., Murayama M., Seok H., Sotiropoulos I., Kim E., Collingridge G.L., Takashima A. and Cho K. (2013) Microtubule associated protein tau (MAPT) is essential for long-term depression in the hippocampus. Phil. Trans. R. Soc. B 369, 2013144. |
Start Year | 2013 |
Description | Bristol-IBS collaboration |
Organisation | Korea Advanced Institute of Science and Technology (KAIST) |
Country | Korea, Republic of |
Sector | Academic/University |
PI Contribution | N/A |
Collaborator Contribution | AMPA receptor shRNA constrcuts and point mutations. |
Impact | Whitehead G., Jo J., Hogg E.L., Piers T.M., Kim D.H., Seaton G., Seok H., Bru-Mercier G., Son G.H., Regan P., Hildebrandt L., Waite E., Kim B.C., Kerrigan T.L., Kim K., Whitcomb D.J., Collingridge G.L., Lightman S.L., Cho K. (2013). Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus. Brain 136, 3753-3765. Kimura K., Whitcomb D.J., Jo J., Regan R., Piers T., Heo S., Brown C., Hashikawa T., Murayama M., Seok H., Sotiropoulos I., Kim E., Collingridge G.L., Takashima A. and Cho K. (2013) Microtubule associated protein tau (MAPT) is essential for long-term depression in the hippocampus. Phil. Trans. R. Soc. B 369, 2013144. |
Start Year | 2013 |
Description | Korea Alzheimer's disease research consortium |
Organisation | Seoul National University |
Country | Korea, Republic of |
Sector | Academic/University |
PI Contribution | UK-Korea collaboration in Neurodegeneration under the Korean Ministry of Health and Welfare. |
Collaborator Contribution | Research tool (miRNA) |
Impact | Lee M., Kim K., Kwon J. H., An O. B., Ryu K., Cho, K., Suh, Y. H. and Kim, H. S. (2012) An activity-regulated microRNA, miR-188, controls dendritic plasticity and synaptic transmission by downregulating neuropilin-2. J of Neurosci 32, 5678-5687. |
Start Year | 2012 |
Description | 60th Neurobiology symposium for the Korean Society for Biochemistry and Molecular Biology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Discussion afterwards N/A |
Year(s) Of Engagement Activity | 2009 |
Description | 7th International Symposium on Geriatrics and Gerontology |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Discussion afterwards N/A |
Year(s) Of Engagement Activity | 2011 |
Description | 8th UK-Korea Neuroscience Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | 120 audience attended for UK-Korea Neuroscience Symposium in Cambridge. Symposium discussed about "new concepts of neuroscience for basic research and therapeutic advances". UK-Korea finding agent (MRC and KHIDI) recognised the value of science in UK and Korea, MRC-KHIDI made new joint grant call for UK-Korea collaboration scheme. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.ukorea.ac.uk/files/2015/09/8TH-UKOR-Programme-2015.pdf |
Description | Bio-Korea Forum |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Policy was made N/A |
Year(s) Of Engagement Activity | 2010 |
Description | British Neuroscience Roadshow in Korea |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Recognition of British Neuroscience research and requested a lot of question. After this event, many of PG application (MSc/PhD) from South Korea |
Year(s) Of Engagement Activity | 2008 |
Description | FENS Satellite Symposium Geneva |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Talk generated questions and discussion Korean Scientists visit my lab and established formal collaboration |
Year(s) Of Engagement Activity | 2008 |
Description | Forum of European Neuroscience(FENS), Amsterdam |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Discussion afterwards. N/A |
Year(s) Of Engagement Activity | 2010 |
Description | Irish Neuroscience Society annual meeting |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussion afterwards Undergraduate students visit my lab from Dublin |
Year(s) Of Engagement Activity | 2011 |
Description | Korean TV (KBS)-Ageing and Dementia talk |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | TV presentation live programme. N/A |
Year(s) Of Engagement Activity | 2014 |
Description | Leibniz Institute for Neurobiology Symposium for Neural Plasticity, Germany |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussion afterwards N/A |
Year(s) Of Engagement Activity | 2012 |
Description | London Health Forum |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Policymakers/politicians |
Results and Impact | Discussion afterwards N/A |
Year(s) Of Engagement Activity | 2013 |
Description | The Royal Society London LTP40 meeting, London |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked questions N/A |
Year(s) Of Engagement Activity | 2013 |