GABAB receptors in the hippocampus: allosteric modulation and receptor isoforms.
Lead Research Organisation:
University of Surrey
Department Name: Health and Medical Sciences
Abstract
The GABAB receptors belong to a family of specialised brain signalling molecules sensing the inhibitory neurotransmitter GABA. The GABAB receptors have been shown to participate in essential functions of the nervous system, like pain sensation, reward and learning and memory, and are hence important therapeutic targets for various diseases, including spasticity, epilepsy, pain and addiction. Baclofen (Lioresal), a molecule that can activate the GABAB receptors, is a muscle relaxant and currently used clinically to treat spasticity. Recently, molecules were also identified to enhance the function of the GABAB receptors by an alternative way of allosteric modulation, and these molecules were found effective in treating addiction and anxiety in animal models. These GABAB receptor potentiators may, thus, become a new class of therapeutics for psychiatric and neurological disorders. However, the detailed mechanisms underlying the actions of these new GABAB potentiators are still poorly understood. In this basic scientific project, we designed a series of experiments aiming to elucidate the mechanisms of the GABAB potentiators in neuronal signalling. Detailed electrophysiological and pharmacological characterization combined with genetic manipulations on GABAB receptor expression will be carried out in the context of neuronal signalling in brain tissues. The further understanding of the GABAB receptor functional modulations will aid the development of newer and more effective drugs for psychiatric and neurological disorders with reduced side effects. Major pharmaceutical companies have shown keen interests in this new drug target.
Technical Summary
This project aims to elucidate the mechanisms underlying GABAB receptor allosteric modulation in synaptic transmission in the hippocampus. GABAB receptor functional heterogeneity was hypothesised to underlie a differential effect on hippocampal synaptic transmission exerted by the GABAB allosteric modulator, CGP7930. Using whole cell voltage clamp recordings in hippocampal slices, the effects of CGP7930 will be examined at GABAB receptors located at different synaptic locations: pre- versus postsynaptic and auto- versus heteroreceptors, in the CA1 areas. Any functional heterogeneity in terms of allosteric modulation will then be identified at the receptors at different synaptic locations. The molecular substrate underlying the GABAB receptor heterogeneity is not yet confirmed, but the two major GABAB receptor isoforms, the 1a and 1b, were suggested to be strong candidates and they were shown to express differentially in the hippocampal CA1 area. Mice with the GABAB 1a or 1b selective deletions will thus be examined regarding the roles of each isoform in synaptic transmission and their responses to GABAB allosteric modulator and GABAB agonists. These results will allow us to elucidate whether the GABAB receptor functional heterogeneity, especially in allosteric modulation, is associated with a particular isoform and/or the expression locations of the isoforms. To demonstrate the physiological relevance of the GABAB allosteric modulation, we will examine the effects of an allosteric modulator on intrinsic GABAB receptor - mediated control of neuronal hyperexcitability and rhythmic activity at the hippocampal network level.
People |
ORCID iD |
Ying Chen (Principal Investigator) |
Publications
Foster JD
(2013)
GABAB receptor subtypes differentially modulate synaptic inhibition in the dentate gyrus to enhance granule cell output.
in British journal of pharmacology
Wu C
(2014)
Local receptors as novel regulators for peripheral clock expression.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Description | We found that the two variants of a receptor in the brain called the GABAB receptor play different roles in synaptic modulation and induction of seizures. By targeting the variant responsible for regulating seizures selectively, a new anti-seizure drug can be developed. We have also developed a novel mathematical analysis to detect and quantify epileptiform activity. |
Exploitation Route | Pharmaceutical industries can use the findings to develop anti-seizure medicines. Health care professionals can look into GABAB receptor variants as a genetic cause of seizures in patients. |
Sectors | Education Healthcare Pharmaceuticals and Medical Biotechnology |
Description | communicated in a number of scientific conferences. Published journal papers. communicated with pharmaceutical industry. Trained a number of young scientists and undergraduate students. |
First Year Of Impact | 2007 |
Sector | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | The emerging role of GABAB receptors as regulators of network dynamics: fast actions from a 'slow' receptor? |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in systematic reviews |
Description | BPS pump-priming |
Amount | £9,583 (GBP) |
Organisation | British Pharmacological Society (BPS) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2014 |
End | 08/2015 |
Title | epileptiform activity in absence of either GABAB receptor subtype |
Description | A novel way to investigate endogenous roles of GABAB receptor subtypes in epileptogenesis |
Type Of Material | Model of mechanisms or symptoms - in vitro |
Provided To Others? | No |
Impact | not yet shown |
URL | http://onlinelibrary.wiley.com/doi/10.1111/bph.12073/full |
Description | Local receptor as a novel regulator for peripheral clock expression |
Organisation | University of Surrey |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I proposed the multidisciplinary research topic and the used of the transgenic mice. |
Collaborator Contribution | Dr Wu is an expert in bladder physiology and his group conducted the bladder experiments. |
Impact | • Wu C, Sui G, Archer S, Sassone-Corsi, P, Aitken D, Bagli D, Chen Y (2014) Local receptors as a novel regular for period 2 activity in the urinary bladder. FASEB J. 2014 Aug 21. pii: fj.13-243295. |
Start Year | 2010 |
Description | non-linear Lempel-Ziv (LZ) complexity analysis to quantify firing rhythmicity in epileptiform potentials |
Organisation | University of Surrey |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | collection of epileptiform data and pharmacological effects |
Collaborator Contribution | develop a LZ complexity algorithm to analyse and quantify firing rhythmicity in epileptiform potentials |
Impact | • Abasolo D, Gonzalez L, Chen Y. (2014) Complexity of epileptiform activity in a neuronal network and pharmacological intervention. IFMBE Proceedings. 41: 575-578. Baclofen Suppresses Epileptiform Activity by Disrupting Spiking Rhythmicity Ying Chen, Lidia Gonzalez, Daniel Abasolo Oral presentation at Pharmacology 2013 http://www.pa2online.org/abstract/abstract.jsp?abid=31271&author=chen&cat=-1.=55 |
Start Year | 2012 |
Description | use of GABAB receptor isoform KO mice |
Organisation | University of Basel |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | We examined GABAB receptor isoforms relating to epileptogenesis. |
Collaborator Contribution | Prof. Bettler provided GABAB receptor isoform KO mice, GABAB1a-/- and GABAB21b-/-. |
Impact | • Abasolo D, Gonzalez L, Chen Y. (2014) Complexity of epileptiform activity in a neuronal network and pharmacological intervention. IFMBE Proceedings. 41: 575-578. • Foster JD, Kitchen I, Bettler B, Chen Y (2013) GABAB receptor subtypes differentially modulate synaptic inhibition in the dentate gyrus to enhance granule cell output. British Journal of Pharmacology, http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1476-5381/accepted |
Start Year | 2006 |
Title | non-linear Lempel-Ziv (LZ) complexity analysis (Lempel and Ziv, 1976) to quantify firing rhythmicity in epileptiform potentials |
Description | The LZ complexity algorithm involves converting the original time series into a discrete sequence of a finite num-ber of symbols. In this study the median was used as the threshold Td in the sequence conversion, given that the me-dian is robust to outliers [Na02]. A sequence P = s(1), s(2),?, s(n) is created by comparison the original signal with the threshold, with s(i) given by: (1) Once this coarse-grained sequence has been created from the original signal, P is scanned from left to right and the complexity counter c(n) is increased by one unit every time a new subsequence of consecutive characters is encountered. A detailed description of the complexity algorithm can be found in [Zh01]. The complexity algorithm is dependent on the sequence length. For this reason, c(n) should be normalized. For a sequence of length n and an alphabet of ? symbols, the upper bound of c(n) is given by [LZ76]: (2) where ?n is a small quantity and ?n ? 0 (n ? ?). In general, (3) Therefore, c(n) can be normalized via b(n): (4) C(n) is then the normalized LZ complexity. Greater C(n) values correspond to more complexity in the data. |
Type Of Technology | Software |
Year Produced | 2013 |
Impact | the analysis can detect and quantify firing rhythmicity in epileptiform potentials. We found that GABAB receptor activation suppressed bicuculline-induced epileptiform activity in the dentate gyrus by decreasing firing rhythmicity, revealing a novel antiepileptic action for GABAB receptor agonists. Furthermore, this novel approach of using LZ complexity analysis may be further explored to discover new antiepileptic targets. |
URL | http://link.springer.com/chapter/10.1007/978-3-319-00846-2_142#page-1 |
Description | Baclofen suppresses epileptiform activity by disrupting spiking rhythmicity |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | the talk sparked questions and discussion afterwards spark similar research, provide new understanding |
Year(s) Of Engagement Activity | 2007,2013 |
URL | http://www.pa2online.org/abstract/abstract.jsp?abid=31271&author=chen&cat=-1&period=55 |
Description | Differential expression and function of GABAB receptor isoforms in the dentate gyrus |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | Yes |
Type Of Presentation | poster presentation |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | The aim of this study is to investigate the differential expression patterns and functional effects of the GABAB receptor isoforms in the hippocampal dentate gyrus. Male BALB/c wild-type, GABAB1a -/- and GABAB1b -/- mice were used for electrophysiological or immunohistochemical investigations. Free floating immunoperoxidase labelling of the GABAB1 and GABAB2 receptor subunits was performed on coronal brain sections using antibodies directed against the GABAB2 subunits. Results showed distinct l no actual impacts realised to date |
Year(s) Of Engagement Activity | 2009 |
Description | GABAB Receptor Subtypes Differentially Affect Synaptic Inhibition in the Dentate Gyrus Foster JD, IK, BB, YC |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | Yes |
Type Of Presentation | poster presentation |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | We examined the function and localisation of GABAB receptors in the dentate gyrus of GABAB1 isoform knockout mice using multielectrode electrophysiological recordings and immunohistochemical labelling. By selective expression in interneurons and their projections, GABAB receptor subtypes may, therefore, differentially modulate synaptic inhibition. The work was supported by the BBSRC. no actual impacts realised to date |
Year(s) Of Engagement Activity | 2009 |
Description | GABAB receptor isoforms differentially modulate the Schaffer collateral - CA1 synaptic transmission in the CA1 of the hippocampal slices. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | The aim of this study is to investigate the differential expression patterns and functional effects of GABAB receptor isoforms in the hippocampus. Male adult BALB/c wild-type (WT), GABAB1a -/- or GABAB1b -/- mice were used for electrophysiological investigations. Field excitatory postsynaptic potentials (fEPSPs) from CA1 stratum radiatum were recorded in response to paired stimuli using a multi-electrode device (MED64). The results show that the GABAB1a but not the GABAB1b receptor subtype no actual impacts realised to date |
Year(s) Of Engagement Activity | 2008 |
Description | GABAB receptor subtypes differentially modulate chemoconvulsant-induced seizure |
Form Of Engagement Activity | Scientific meeting (conference/symposium etc.) |
Part Of Official Scheme? | Yes |
Type Of Presentation | poster presentation |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | GABAB receptors are strongly implicated in the genesis and spread of seizures1, however, the precise roles of GABAB receptor subtypes that are located at different synaptic compartments2 and neuronal networks are yet to be defined. In mice lacking either the GABAB1a or GABAB1b isoforms2, we examined the roles of the GABAB(1a,2) and GABAB(1b,2) receptors in the development of seizure. Epileptic behaviours in mice were triggered by an injection (subcutaneous route at 60 mg/kg) of a chemoconvuls no actual impacts realised to date |
Year(s) Of Engagement Activity | 2010 |
URL | http://www.pa2online.org/abstract/abstract.jsp?abid=29629&kw=GABA&author=chen%20y&cat=-1&period=45 |
Description | media interest (circadian rhythm in bladder) |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | sparked many reports in popular media and patient groups: http://www.healthylivingmagazine.us/Articles/2104/ http://www.sciencedaily.com/releases/2014/10/141030114951.htm http://forums.phoenixrising.me/index.php?threads/treatment-for-overactive-bladder-and-irritable-bowel-syndrome-advanced-through-pioneering-research.32139/ http://naturalhomeremedyreviews.com/overactive-bladder-treatment/ not yet known |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.surrey.ac.uk/mediacentre/press/2014/130384_treatment_for_overactive_bladder_and_irritable... |