Regulation of synaptic inhibition by GABAA receptor trafficking under normal conditions and in neurological and neuropsy
Lead Research Organisation:
University College London
Department Name: Neuroscience Physiology and Pharmacology
Abstract
Nerve cells send signals to each other by releasing chemicals called neurotransmitters at special sites called synapses. The neurotransmitters act on special proteins (receptors), allowing ions to cross the cell membrane, thus producing voltage changes across the membrane. My application is on two key aspects of brain function: (i) how neurons regulate the number of neurotransmitter receptor proteins present at synapses to control the size of the membrane voltage changes; and (ii) how this regulation may be altered in disease processes. Studying the molecular mechanisms that underlie these regulatory processes will allow us to understand better how the brain works under healthy conditions, and how dysregulation of these processes leads to altered electrical behaviour of nerve cells in disease. This work could lead the way to the development of new therapies in devastating diseases such as epilepsy, stroke, anxiety, Huntington‘s disease, substance abuse, depression, Parkinson‘s disease and autism.
Technical Summary
The activity of GABAA receptors (GABAARs)s at inhibitory synapses is critical for maintaining the correct balance between excitation and inhibition of neurons. The strength of inhibitory synapses, and thus neural information processing, can be modulated by altering the trafficking of GABAARs into or out of the postsynaptic membrane. Altered GABAAR activity and trafficking are also implicated in many neurological and psychiatric diseases including epilepsy, stroke, Huntington‘s disease, anxiety, drug addiction, depression and schizophrenia. Thus, understanding how the strength of inhibitory synapses is controlled by GABAAR trafficking is crucial for understanding how the brain works, and may also lead to the identification of therapeutic interventions in a wide range of diseases.
Using novel imaging, molecular, cell biological and electrophysiological techniques, I will determine the molecular mechanisms that control GABAAR trafficking. I will focus on how covalent modification of GABAARs (e.g. by phosphorylation and ubiquitination) and interaction with GABAAR associated proteins (AP2, HAP1 and the novel ubiquitin ligase, Guapa) regulates surface receptor mobility (lateral diffusion and dwell time at synapses) and GABAAR trafficking to and from the membrane (exocytosis, endocytosis and degradation) to control inhibition under resting conditions, during neural activity, during homeostatic plasticity and in diseases like epilepsy.
A major aim will be to develop novel imaging techniques to study receptor lateral diffusion and trafficking (such as receptor tracking with Quantum Dots) to study trafficking processes in intact tissues such as brain slices from animal models of neurological disease.
A second major aim will be to determine if the pathological GABAAR internalization that occurs during status epilepticus, which leads to rapid resistance to drugs used to treat status, can be inhibited by targeting the GABAAR endocytic and degradation machineries. This could lead to novel therapeutic interventions for this devastating disease.
A third major aim will be to determine if HAP1-dependent GABAAR trafficking is important for inhibitory homeostatic plasticity, to test whether this is disrupted by mutant huntingtin (which causes Huntington‘s disease) and to determine whether HAP1 function is regulated by the schizophrenia susceptibility genes DISC1 and dysbindin.
This work will provide fundamental insights into the mechanisms that regulate the number of GABAA receptors at synapses normally and during synaptic plasticity, and may also lead to new information regarding the cell biology of a number of proteins critically implicated in neurological and psychiatric diseases.
Using novel imaging, molecular, cell biological and electrophysiological techniques, I will determine the molecular mechanisms that control GABAAR trafficking. I will focus on how covalent modification of GABAARs (e.g. by phosphorylation and ubiquitination) and interaction with GABAAR associated proteins (AP2, HAP1 and the novel ubiquitin ligase, Guapa) regulates surface receptor mobility (lateral diffusion and dwell time at synapses) and GABAAR trafficking to and from the membrane (exocytosis, endocytosis and degradation) to control inhibition under resting conditions, during neural activity, during homeostatic plasticity and in diseases like epilepsy.
A major aim will be to develop novel imaging techniques to study receptor lateral diffusion and trafficking (such as receptor tracking with Quantum Dots) to study trafficking processes in intact tissues such as brain slices from animal models of neurological disease.
A second major aim will be to determine if the pathological GABAAR internalization that occurs during status epilepticus, which leads to rapid resistance to drugs used to treat status, can be inhibited by targeting the GABAAR endocytic and degradation machineries. This could lead to novel therapeutic interventions for this devastating disease.
A third major aim will be to determine if HAP1-dependent GABAAR trafficking is important for inhibitory homeostatic plasticity, to test whether this is disrupted by mutant huntingtin (which causes Huntington‘s disease) and to determine whether HAP1 function is regulated by the schizophrenia susceptibility genes DISC1 and dysbindin.
This work will provide fundamental insights into the mechanisms that regulate the number of GABAA receptors at synapses normally and during synaptic plasticity, and may also lead to new information regarding the cell biology of a number of proteins critically implicated in neurological and psychiatric diseases.
People |
ORCID iD |
Josef Thomas Kittler (Principal Investigator / Fellow) |
Publications


Atkin T
(2012)
DISC1 and the aggresome: a disruption to cellular function?
in Autophagy

Atkin TA
(2011)
Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons.
in Molecular psychiatry

Atkin TA
(2012)
Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport.
in Human molecular genetics

Birsa N
(2014)
Lysine 27 ubiquitination of the mitochondrial transport protein Miro is dependent on serine 65 of the Parkin ubiquitin ligase.
in The Journal of biological chemistry

Burzomato V
(2010)
The receptor subunits generating NMDA receptor mediated currents in oligodendrocytes.
in The Journal of physiology

Couve A
(2014)
Preface. Trafficking of organelles and proteins in the nervous system.
in Seminars in cell & developmental biology

Covill-Cooke C
(2020)
Regulation of peroxisomal trafficking and distribution.
in Cellular and molecular life sciences : CMLS

Davenport EC
(2017)
An Essential Role for the Tetraspanin LHFPL4 in the Cell-Type-Specific Targeting and Clustering of Synaptic GABA Receptors.
in Cell reports

Davenport EC
(2019)
Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition.
in Cell reports
Description | As part of this work we demonstrated the rapid delivery of GABAA receptors to synapses from internal pools is mediated by a motor protein complex comprising the huntingtin associated protein 1 (HAP1) and kinesin motor protein KIF5. This work, which included collaborations with Zhen Yan (SUNY, USA), Frederic Saudou (Institute Curie, France) and Antoine Triller (ENS, France), resolved a key outstanding issue in the field regarding how GABAA receptor containing transport vesicles are delivered to synapses from internal stores. This work also demonstrated that the HAP1-KIF5 complex is a locus of altered GABAA receptor transport leading to pathological disinhibition in Huntington's disease models (Twelvetrees et al., 2010; Neuron). Follow on work also identified an importance of the HAP1-KIF5 complex for the trafficking of other ion channels including AMPA receptors (Mandal et al., 2011, JBC). In ongoing work in this area we have elucidated novel roles for HAP1 as a direct activator of the KIF5 motor protein (Manuscript in preparation). |
Exploitation Route | Our findings form the basis of detailed mechanistic understanding of the formation and maintenance of inhibitory synapses. This can then form the basis of fixture experiments to determine how these processes go awry in neuropathology. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | MRC Case Award |
Amount | £75,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2011 |
End | 09/2014 |
Title | Single molecule imaging with Quantum Dots |
Description | Funding allowed us to continue to develop 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 | Data analysis technique |
Provided To Others? | No |
Impact | This approach was used to study receptor membrane dynamics as described in our recent publication: Muir et al., 2010 PNAS. |
Description | Collaboration on the function of Disc1 and PCM1 in Schizophrenia and major mental illness |
Organisation | University College London |
Department | Neuroscience, Physiology & Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Analysis of neuronal function of Schizophrenia susceptibility genes Disc1 and PCM1 |
Collaborator Contribution | Collaborators have provided important expertise in human molecular genetics |
Impact | Joint application for an MRC programme grant (Hugh Gurling lead PI). |
Start Year | 2009 |
Description | Collaboration with Matthew Walker |
Organisation | University College London |
Department | School of Life and Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing high resolution microscopy imaging expertise |
Collaborator Contribution | Providing expertise on rodent and in vitro models of epilepsy |
Impact | Joint publication |
Start Year | 2011 |
Description | Collaboration with Pfizer |
Organisation | Pfizer Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | Expertise in imaging and neurobiology |
Collaborator Contribution | Commitment from Pfizer 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 leading to successful award of an MRC Case studentship. in form of MRC case studentship application - pending |
Start Year | 2010 |
Description | Developing techniques for studying receptor membrane dynamics with single molecule Quantum Dot imaging |
Organisation | University College London |
Department | Department of Computer Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Application of nanotechnology to receptor imaging. Developed platform for imaging signals from Quantum Dot labelled GABA-A receptors. |
Collaborator Contribution | Allowed the development and application of computer vision techniques to imaging and analysis of single molecule tracking of Quantum Dots |
Impact | Data from this collaboration has been presented at several international meetings. These approaches have lead to new findings regarding the membrane dynamics of GABA-A receptors recently published - Muir et al., 2010 PNAS |
Start Year | 2006 |
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 | Neuromouse consortium - Doug Turnbull |
Organisation | Newcastle University |
Department | Institute for Ageing and Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Contributing member of Neuromouse consortium bid for generation and phentoyping of novel mouse lines relevant to human disease which was recently awarded. |
Collaborator Contribution | Neuromouse consortium will provide access to novel mouse transgenic lines and access to phenotyping expertise. |
Impact | Lead to succesfull MRC mouse consortium bid. |
Start Year | 2011 |
Description | In2Science UK |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 1-2 week laboratory placement scheme in the summer for gifted A-level science students from disadvantaged backgrounds (the poorest 10% of our society). Stimulated thinking of future young scientist |
Year(s) Of Engagement Activity | 2013 |
Description | Newsletter article |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Primary Audience | Health professionals |
Results and Impact | Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, Rostaing P, Lumb MJ, Triller A, Saudou F, Yan Z, Kittler JT (2010) Delivery of GABAA receptors to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron. 65:53-65. Journal impact factor 14.2 (Web of Science 2008). This paper, details for the first time the mechanisms that underlie the rapid delivery of inhibitory GABAA receptors to synapses. The work shows that a motor protein complex consisting of microtubule motors and an adaptor protein called the huntingtin associated protein 1 (HAP1) deliver GABAA receptor transport vesicles to inhibitory synapses to change the strength of these synapses. The study also reveals that when the HAP1 interacting partner huntingtin is mutated, as in Huntington's disease, GABAA receptor transport is impaired which may contribute to altered information processing in Huntington's. This work was highlighted in the April issue of the MRC bi-monthly magazine MRC Network (http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC006687). None |
Year(s) Of Engagement Activity | 2010 |
Description | Participated in In2Science UK |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 1-2 week laboratory placement scheme in the summer for gifted A-level science students from disadvantaged backgrounds (the poorest 10% of our society). Impacted on students interest in biomedical research. |
Year(s) Of Engagement Activity | 2011 |
Description | Poster presentation and Gold Medal Winner House of Commons SET for Britain |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Policymakers/politicians |
Results and Impact | SET for Britain is a competition in the House of Commons which involves researchers displaying posters of their work to panels of expert judges and more than 100 MPs. The event aims to help politicians understand more about the UK's thriving science base and rewards some of the strongest scientific research being undertaken in the UK. Dr Atkin won the Gold Prize Medal for her presentation. This is also lead to some media interest |
Year(s) Of Engagement Activity | 2010 |
Description | Website dissemination |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Primary Audience | Public/other audiences |
Results and Impact | Twelvetrees AE, Yuen EY, Arancibia-Carcamo IL, Rostaing P, Lumb MJ, Triller A, Saudou F, Yan Z, Kittler JT (2010) Delivery of GABAA receptors to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron. 65:53-65. Journal impact factor 14.2 (Web of Science 2008). This paper, details for the first time the mechanisms that underlie the rapid delivery of inhibitory GABAA receptors to synapses. The work shows that a motor protein complex consisting of microtubule motors and an adaptor protein called the huntingtin associated protein 1 (HAP1) deliver GABAA receptor transport vesicles to inhibitory synapses to change the strength of these synapses. The study also reveals that when the HAP1 interacting partner huntingtin is mutated, as in Huntington's disease, GABAA receptor transport is impaired which may contribute to altered information processing in Huntington's. This work was highlighted on the UCL website (http://www.ucl.ac.uk/news/news-articles/from-neuroscience/10012001). N/A |
Year(s) Of Engagement Activity | 2010 |