Regulation of synaptic inhibition under normal conditions and in ischaemia and neurodegenerative disease

Lead Research Organisation: University College London
Department Name: Neuroscience Physiology and Pharmacology

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Synaptic inhibition, mediated by the -aminobutyric acid type A receptor (GABAAR), a ligand-gated chloride channel, is crucial for the control of cell and network activity in the brain. Modulating GABAAR function has major consequences for neuronal excitation and information processing in the brain. In addition, altered GABAAR function has been implicated in an increasing number of neurological and neuropsychiatric diseases. Understanding the molecular mechanisms neurons use to regulate GABAAR function will have important implications for both our understanding of how neuronal activity is controlled and how disrupted inhibition may contribute to the pathogenesis of diseases such as epilepsy, stroke, anxiety, substance abuse, depression, Parkinson‘s disease and autism. One accepted means of modifying the efficacy of synaptic transmission is to change the number and/or sensitivity of postsynaptic receptors. This can be achieved by a number of mechanisms, including regulated receptor membrane trafficking, and post-translational modifications such as phosphorylation, ubiquitination or palmitoylation. The overall aim of my research is to understand better the molecular mechanisms important for regulating GABAAR function, with a particular emphasis on control of GABAAR membrane trafficking and how this may be altered under pathological conditions such as ischaemia and neurodegeneration. The main objectives of my proposal are to investigate three distinct but related questions:
(1) How do glutamate signalling and ischaemia modulate GABAAR activity, surface dynamics and membrane trafficking?
(2) What is the role of the huntingtin associated protein 1 (HAP1) in GABAAR membrane trafficking?
(3) Does disrupted HAP1 function lead to altered GABAAR activity in Huntington‘s disease (HD)?
Completion of this work will provide valuable insights into how GABAAR function and synaptic inhibition are controlled under normal conditions, and how altered inhibitory neurotransmitter ptor function and trafficking may contribute to neuronal dysfunction in stroke and neurodegenerative disease.
To answer these questions, I will use a multi-disciplinary approach combining molecular, cell biological, biochemical, imaging and electrophysiological methodologies.

Publications

10 25 50
publication icon
Arancibia-Cárcamo IL (2009) Ubiquitin-dependent lysosomal targeting of GABA(A) receptors regulates neuronal inhibition. in Proceedings of the National Academy of Sciences of the United States of America

publication icon
Arancibia-Cárcamo IL (2009) Regulation of GABA(A) receptor membrane trafficking and synaptic localization. in Pharmacology & therapeutics

publication icon
Chen G (2006) Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. in The Journal of neuroscience : the official journal of the Society for Neuroscience

publication icon
Jacob TC (2005) Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. in The Journal of neuroscience : the official journal of the Society for Neuroscience

publication icon
Kastning K (2007) Molecular determinants for the interaction between AMPA receptors and the clathrin adaptor complex AP-2. in Proceedings of the National Academy of Sciences of the United States of America

publication icon
Kittler JT (2008) Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor gamma2 subunit. in Proceedings of the National Academy of Sciences of the United States of America

 
Description MRC Senior Non-Clinical Fellowship
Amount £2,000,000 (GBP)
Funding ID G0802377 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 01/2015
 
Description Royal Society Research Grant
Amount £15,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 01/2006 
End 01/2007
 
Title Analysis of Quantum Dot tracking 
Description Funding allowed the establishment in my group of state of analysis approaches 9in collaboration with Dr Lewis Griffin) to analyse imaging data of single neurotransmitter receptors in the plasma membrane of nerve cells imaged using Quantum Dots. 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact lead to additional MRC fellowship funding 
 
Title Imaging with Quantum Dots 
Description Funding allowed the establishment in my group of state of the art imaging approaches to study the behavior of single neurotransmitter receptors in the plasma membrane of nerve cells. These approaches used novel technologies such as semi conductor nanocrystals (Quantum Dots). 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The establishment of these approaches during the tenure of my MRC Career Development Award was a direct contributor to my successful application for an MRC Senior-Non Clinical Fellowship. 
 
Description Collaboration with Pfizer 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Expertise in imaging and neurobiology
Collaborator Contribution Commitment to financial support and provision of proprietary reagents for future work in form of MRC case studentship application - pending.
Impact Commitment from Pfizer to financial support and provision of proprietary reagents for future work in form of MRC case studentship application - pending
Start Year 2010
 
Description Imaging receptor membrane dynamics with Quantum Dots 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Lead research on receptor membrane dynamics in nerve cell membranes
Collaborator Contribution Provided novel methods for acquisition and analysis of ion channels at the membrane of nerve cell labelled with semi conductor nanocrystals
Impact Data from this collaboration has been presented at several international meetings. Data currently being written up for publication. The methods derived from this collaboration directly contributed to a successful application for an MRC Senior Non-Clinical Fellowship
Start Year 2006
 
Description Molecular determinants of ion channel interaction with AP2 
Organisation Free University of Berlin
Department Department of Biochemistry
Country Germany 
Sector Academic/University 
PI Contribution Lead research project to identify molecular determinants of interaction between GABA-A receptor and the clathrin adaptor AP2 (Kittler et al., 2008). Contributed to research project on identification of molecular determinants of AMPA receptor interaction with AP2 (Kastning et al., 2007).
Collaborator Contribution Contributed reagents, biochemical analysis and x-ray crystallography expertise
Impact Lead to invitations to present research at several institutions and to several publications in leading journals (e.g. Kittler et al 2008; Kastning et al 2007). Additional data is currently being written up for publication. This work also directly contributed to a successful application for an MRC senior non-clinical fellowship.
 
Description Physiological role of GABA-A and glutamate receptor plasma membrane endocytosis 
Organisation University at Buffalo
Department Department of Physiology and Biophysics
Country United States 
Sector Academic/University 
PI Contribution Lead research project on GABA-A receptor endocytosis and it's physiological consequences for synaptic transmission (Kittler et al., 2008). Contributed to research project on study of physiological role of AMPA receptor internalisation for synaptic transmission (Kastning et al., 2007).
Collaborator Contribution Provided expertise in electrophysiological analysis of synaptic transmission.
Impact Lead to invitations to present research at several institutions and to several publications in leading journals (e.g. Kittler et al 2008; Kastning et al 2007). Additional data is currently being written up for publication. This work also directly contributed to a successful application for an MRC senior non-clinical fellowship.
 
Description Website dissemination 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Our work was also showcased in the MRC News section of the MRC website (see (http://www.mrc.ac.uk/Newspublications/News/MRC005717).

Led to work being promoted by UCL Neurosciences promotion of brain awareness week.
Year(s) Of Engagement Activity 2009
 
Description Website dissemination 
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 'UCL neuroscience' (www.ucl.ac.uk/neuroscience) which brings together neuroscience research at UCL has a very active public engagement policy. UCL was recently named one of the six 'Beacons of Public Engagement' nationwide. As part of UCL Neurosciences promotion of brain awareness week 2009, UCL neuroscience showcased work from several labs including our work 'Brain power where it is needed' as part of the 'latest breakthroughs' for UCL neuroscience (see http://www.ucl.ac.uk/news/news-articles/0903/09031604).

NA
Year(s) Of Engagement Activity 2009