GABAB receptors in the hippocampus: allosteric modulation and receptor isoforms.

Lead Research Organisation: University of Surrey
Department Name: Unlisted

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.

Publications

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publication icon
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 09/2014 
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...