The laboratory employs a multidisciplinary approach utilising the techniques of electrophysiology, biochemistry, molecular biology and behaviour. Current research topics include:
The development of novel anxiolytics and pro-cognitive agents.
The GABAA receptor (GABAAR) is an important therapeutic target for drugs such as diazepam. Diazepam binds to a specific site on the GABAAR to enhance the interaction of GABA with the receptor (a positive allosteric modulator – PAM). An important clinical application of diazepam and related benzodiazepines is in the treatment of anxiety. However, the use of such drugs is limited by their side-effect profile, which may include sedation, impaired cognition, tolerance and addiction. The discovery that distinct GABAAR isoforms mediate these various behaviours has encouraged the development of a new generation of GABAAR subtype-selective drugs. In an MRC-funded collaboration, with Professors Atack and Ward (Cardiff University), we are involved in a drug discovery programme to develop novel anxiolytics, which do not cause sedation.
The memory-impairing effects of diazepam appear to be primarily due to the drug acting to enhance the function of the α5-GABAAR subtype. Indeed, α5-GABAAR inhibitors exhibit cognitive enhancing properties. In a Wellcome Trust funded collaboration with Cardiff University, we are involved in the development of novel α5-GABAAR inhibitors to treat the cognitive impairment associated with conditions such as Huntington’s disease (see below). Inhibitors of α5-GABAARs show promise in protecting neurons from damage associated with stroke. In collaboration with Servier (Paris), we discovered S44819, which acts on a site distinct from the benzodiazepine site to selectively inhibit α5-GABAARs. S44819 is currently in clinical trial for treating stroke (Neuropharmacology ; 125: 30-38.)
The molecular mechanism of action of antidepressants.
Depressive disorder is a major psychiatric disease estimated by the World Health Organisation to impair ~ 350 million individuals world-wide. The majority of available antidepressants act to influence the neurotransmitters serotonin and or norepinephrine. However, such treatments require weeks before any benefit is perceived and importantly a substantial proportion of patients show little, or no improvement. Clearly, there is an urgent requirement to evaluate alternative targets for discovering new antidepressant therapeutics. We demonstrated that the clinically used antidepressant tianeptine acts to enhance the function of glutamate-activated AMPA receptors, suggesting an alternative molecular target (Mol. Psychiatry  18(4): 471-484. In support, the rapid antidepressant actions of ketamine have been shown to be mimicked by a ketamine metabolite that enhances AMPA receptor activity. We are currently investigating the role of AMPARs in the actions of novel antidepressants.
Neurosteroids: endogenous regulators of synaptic inhibition.
Our work and that of others has established that certain neurosteroids (metabolites of progesterone and corticosterone) are endogenous, potent, efficacious, allosteric enhancers of the GABAA receptor function that consequently influence our mood and behaviour Nat. Neurosci., Rev. ; 6: 565-575). Perturbations of neurosteroid levels are implicated in stress, anxiety, depression and certain forms of epilepsy. Intriguingly ethanol and certain antidepressants such as fluoxetine (Prozac) enhance neurosteroid levels. Our recent studies are revealing that specific brain neurons can synthesise such neurosteroids, which act in an autocrine manner to “fine tune” neuronal inhibition.
How general anaesthetics produce unconsciousness:
It is difficult to conceive of major surgery without the use of a general anaesthetic such as propofol. However, although used clinically for over 160 years, understanding how general anaesthetics produce their dramatic behavioural effects has proved elusive. With Dr. Delia Belelli we demonstrated that the effect of certain anaesthetics to enhance GABAA receptor function was dictated by the nature of a single amino acid on the GABAAR ß2 subunit. In collaboration we demonstrated that a mouse carrying this ß2 subunit mutation became insensitive to the sedative effects of the anaesthetic and that its’ ability to induce unconsciousness was reduced (J. Neurosci.,  23(24); 8608-17; J. Neurosci.,  25(50): 11513-20). These findings raise the prospect of developing novel anaesthetics with reduced sedative (“hangover”) liability. Furthermore, by comparing the activity of anaesthetics on neuronal activity, in brain regions associated with sleep and consciousness (eg. the thalamus) in both normal and “sedative-resistant” models we are beginning to understand how such agents produce their dramatic behavioural effects (J. Physiol., , 586(4): 965-87; Eur. J. Neurosci.,  29(6): 1177-87; J. Neurosci., , 33(9): 3905-14).
Huntington’s disease (HD) is a fatal, often late onset, neurodegenerative disorder that is inherited in an autosomal dominant manner. Although traditionally classed as causing motor dysfunction, it is now recognised that often, prior to the development of such movement disorders, patients present with psychiatric problems and cognitive dysfunction. In collaboration with Professor Susann Schweiger (Mainz), and Dr. Rosamund Langston (Dundee), we are using a mouse model of Huntington’s disease to investigate the impact that mutant huntingtin has on synaptic plasticity and behaviour. Our studies reveal that hippocampal long term potentiation (LTP – an electrophysiological correlate of learning and memory) is compromised in such mice and that this malfunction is accompanied by a deficit in their performance of hippocampal-dependent cognitive tasks. The hippocampus is known to exhibit dense expression of the alpha5-GABAA receptor, which we demonstrated to mediate a tonic inhibitory current in hippocampal CA1 pyramidal neurons (Proc. Natl. Acad. Sci. USA  101(10): 3662-7). In heterozygous HD mice we find an alpha5-GABAA receptor antagonist, enhances LTP and rescues the cognitive deficits, potentially providing a new therapeutic target. In collaboration with Prof Atack (Cardiff) we are involved in a Wellcome Trust drug discovery project to develop novel inhibitors of alpha5-GABAARs to treat this Huntington's disease patients.
The role of GABAA receptors in drug and alcohol addiction:
Collaborators at Sussex University (MRC GABA Cluster; Prof. D Stephens; Dr. S King) demonstrated that the behavioural effects of cocaine are greatly influenced by the presence of the GABAAR alpha2 subunit and studies in Dundee reveal the majority of synaptic inhibition in the medium spiny neurons (MSNs) of the accumbens (a brain region associated with reward and addiction) to be mediated by synaptic alpha2-GABAA receptors (Proc. Natl. Acad. Sci. USA  107: 2289 - 2294). Intriguingly in humans, haplotypes of the alpha2 subunit are associated with both alcohol and drug eg cocaine addiction. This association is particularly evident for individuals with a history of early life stress or trauma. In collaboration with Dr Delia Belelli (Dundee), Prof. D Stephens & Dr. S King (Sussex University) and Dr. J Swinny (Portsmouth University), we are investigating the link between the alpha2 subunit, neuronal function, addiction and childhood trauma. Accumbal MSNs additionally express extrasynaptic GABAARs composed of alpha4, beta and delta subunits, which mediate a tonic, persistent form of inhibition that greatly influences neuronal excitability (J. Neurosci.,  34(3): 823-38). Deletion of the alpha 4 or delta subunit from the accumbens reduces alcohol intake. Importantly, in collaboration with colleagues at Imperial College, University College London, Sussex University and Newcastle University we have uncovered an important role for the GABAAR beta1 subunit in alcohol behaviour (Nat. Commun. , 4: 2816). Two mouse lines were discovered carrying distinct point mutations of the beta1 subunit (Figure 2). In common, both of these mutations resulted in a much increased tonic conductance in the accumbens. Furthermore, mice from both lines showed a greater preference and desire for ethanol over water. These findings demonstrate that excessive drinking can be caused by a single mutation and suggest that these accumbal extrasynaptic receptors as a novel target for treating addiction. In related studies we have identified extrasynaptic glycine receptors as an additional sensitive target for ethanol (Neuropsychopharm, , 33(50): 19534-54).