Murray Herd obtained a BSc (Hons) degree in Biomedical Sciences (Pharmacology) from the University of Aberdeen in 2000. He then moved to the University of Dundee to conduct postgraduate studies in the laboratory of Dr Delia Belelli, where he investigated the influence of certain naturally occurring steroids on inhibitory neurotransmission in the amygdala and hippocampus. On completion of his PhD in 2004, Murray remained in Dundee to work as a post-doctoral fellow in the labs of Dr Delia Belelli and Prof. Jeremy Lambert. During this time, Murray investigated the physiological and pharmacological properties of molecularly distinct subclasses of GABAA receptors in discrete neural networks including the hippocampus, thalamus and nucleus accumbens.
In 2010, Murray was awarded a Fellowship from Epilepsy Research UK to study the activity-dependent properties of inhibition in the thalamic network, with a particular emphasis on the role of extrasynaptic GABAA receptors during network activity relevant to absence epilepsy.
The normal functioning of neurones within the healthy brain depends on a fine balance between the conflicting influences of excitatory and inhibitory neurotransmitters. Indeed, tipping this balance one way or the other, can and does have extraordinary implications for brain behaviours. For example, even subtle alterations of this excitation-inhibition balance within discrete brain regions can lead to an array of neurological and psychiatric conditions, including epilepsy, schizophrenia, anxiety and mood disorders to name only a few. However, the ability to artificially manipulate this balance can also be of great therapeutic value. For example drugs that promote or enhance neuronal inhibition can exert powerful anticonvulsant, sedative, anxiolytic and analgesic effects, and in some cases may act as general anaesthetics. Clearly, therefore, understanding the mechanisms which generate inhibitory neurotransmission in neuronal networks relevant to specific behaviours, is of fundamental importance in both physiological and pathophysiological contexts. Thus, a major goal of the research conducted in our lab has been to understand how the molecular, biophysical and pharmacological properties of neuronal inhibition vary across discrete brain regions, and how such heterogeneity may be tailored to perform specific network-dependent functions.
Neuronal inhibition: a temporal diversity
Fast neuronal inhibition is mediated predominantly by the activation of GABAA receptors (GABAARs) upon binding of the neurotransmitter GABA. Considerable heterogeneity exists between GABAA receptor populations; such variation arises because each receptor is composed of 5 subunits drawn from a pool of 19 different subunit isoforms. Thus, around 20-30 different GABAA receptor subtypes are thought to occur in mammalian brains, with each subtype displaying unique biophysical and pharmacological properties, together with brain region-dependent expression profiles. Indeed, accruing evidence indicates that molecularly distinct sub-populations of GABAA receptor sub-serve specific inhibitory effects on neuronal activity, which can in turn exert important behavioural effects. Specifically, we and others have shown that in some brain regions (e.g. hippocampus and thalamus), GABAARs generate two temporally divergent modes of inhibition, known as phasic and tonic inhibition (Herd et al., 2008, 2009). Classical phasic inhibition is brief in timescale (although the brevity may vary depending on the receptor isoform) and is mediated by synaptically localised GABAARs (Figure 1).
By contrast, tonic inhibition is generated by the activation of peri- or extrasynaptic GABAARs in response to low levels of ambient GABA (Figure 1). The sustained nature of tonic inhibition thus provides a very powerful inhibitory break of neuronal activity, by reducing the sensitivity to excitatory input, whereas the transient nature of phasic inhibition provides temporal precision during integration of neuronal inputs. Interestingly, the molecular structure of d subunit-containing extrasynaptic GABAARs (d-GABAARs, the predominant extrasynaptic receptor isoform) confers not only unique biophysical properties (e.g. high affinity for GABA and reduced desensitisation), but also determines pharmacology. Indeed we have found that such receptors exhibit greater sensitivity to certain neurosteroids, general anaesthetics (e.g. etomidate), some sedative/hypnotic drugs (e.g. gaboxadol), whilst remaining insensitive to benzodiazepines (e.g. diazepam), which potently enhance the function of synaptic receptors (Herd et al., 2008, 2009; Peden et al., 2008). Given the selective expression of d-GABAA receptors in discrete brain networks relevant for behaviours including cognition, attention, reward, memory and the sleep-wake cycle, such studies emphasise the potential of extrasynaptic GABAA receptors as a novel therapeutic target.
Inhibitory control of the thalamic network
Neuronal interplay between the thalamus and cortex underpins an array of behaviours including sensorimotor processing, attention, cognition and control of the sleep wake cycle. In all aspects, the inhibition of thalamocortical (TC) relay neurones is likely to represent a critical factor in the genesis of such behaviours. Importantly, perturbations of thalamic network function have been implicated in a constellation of neurological and psychiatric disorders including absence epilepsy, schizophrenia, sleep disorders and pain disorders (e.g. neuropathic pain). Moreover, given the crucial role of the thalamus in transitions between conscious and unconscious states, the thalamic network may constitute an important neural substrate for hypnotic drugs and general anaesthetics.
The activity of TC relay neurones is tightly regulated by a powerful inhibitory drive provided by GABA-ergic nucleus reticularis neurones of the ventral thalamus. However, it is unclear how the distinct populations of GABAA receptors expressed within synaptic and extrasynaptic domains (Belelliet al., 2005; Peden et al., 2008; Herd et al., 2009) cooperate to influence the function of TC relay neurones, particularly in the face of nRT output which can vary substantially in firing pattern and intensity. To investigate this aspect of thalamic network function I was awarded an ERUK fellowship in 2010. This study has revealed that extrasynaptic GABAA receptors do not simply mediate a static tonic inhibitory conductance, but can additionally be dynamically controlled by the mode and intensity of presynaptic inputs from nRT neurones (Herd et al., 2013). Thus during nRT burst firing (the prevalent firing mode during unconscious states), extrasynaptic GABAA receptors are recruited by neurotransmitter spillover, resulting in a dramatic prolongation of the duration of synaptic inhibition. Moreover, extrasynaptic receptors may also be recruited, in an activity-dependent manner, by tonicaction potential firing (the prevalent nRT firing mode during conscious states), demonstrating that TC neurone tonic conductance may be up- or down-regulated according to the tonic firing intensity of nRT neurones. Importantly, these “burst-mediated spillover” and “tonic-mediate spillover” inhibitory modes are highly sensitive to modulation by selective modulators of extrasynaptic GABAA receptors, revealing novel opportunities for therapeutic intervention in thalamic network disorders. Furthermore, manipulation of GABA transporter systems can dramatically affect the properties of both burst and tonic-mediated spillover. This observation is of some pathophysiological importance, as disruption of GABA transport function has been heavily implicated in the aetiology of experimental absence seizures in several rodent animal models. Given that robust nRT burst firing predominates during spike-wave discharges (the EEG hallmark of absence seizures), it is proposed that novel burst mediated spillover inhibition may play an important role in the development of paroxysmal activity in the thalamocortical network.
Lectures and conferences
Nov 2013: Society for Neuroscience Annual Meeting, San Diego, IL, USA. Poster presentation: Activity-dependent activation of extrasynaptic GABAA receptors revealed by nRT-VB paired recordings.
Sept 2013: International League Against Epilepsy, Glasgow. Platform presentation: The many faces of inhibition in the thalamic network: potential roles in typical absence epilepsy.
August 2013: Scottish Neuroscience Annual Meeting, Edinburgh, UK. Platform presentation: Spillover activation of extrasynaptic GABAA receptors.
August 2012: Scottish Neuroscience Annual Meeting, Dundee, UK. Poster presentation: Dynamic control of extrasynaptic GABAA receptors by presynaptic activity: Evidence from paired nRT-VB recordings in mouse thalamus
Feb 2012: Scottish Epilepsy Group annual meeting, Dundee, UK. Platform presentation: Multiple modes of thalamic inhibition: Potential roles in absence epilepsy
Dec 2011: University of County Cork, Rep of Ireland. Invited seminar. Multiple modes of inhibition in thalamic relay neurones.
Oct 2009: Society for Neuroscience Annual Meeting, Chicago, IL, USA. Poster presentation: Investigating the effects of etomidate on thalamocortical relay neurone excitability: role of synaptic and extrasynaptic GABAA receptors.
Aug 2008: International League Against Epilepsy, UK Annual Meeting, Dundee. Presentation: Modulation of synaptic and extrasynaptic GABAA receptors in thalamic neurones: relevance to the treatment of absence epilepsy.
Nov 2008: Society for Neuroscience Annual Meeting, San Diego, CA, USA. Poster presentation: Developmental plasticity of mouse thalamocortical synaptic and extrasynaptic GABAA receptors.
Feb 2008: Invited speaker at BNA young investigator seminar series of the Neurosciences department, University of Leeds: Developmental maturation of synaptic and extrasynaptic inhibition in thalamocortical relay neurones.
Feb 2007: Scottish Epilepsy Group meeting, University of Dundee. Presentation: GABAA receptors in epilepsy: Synaptic and extrasynaptic GABAA receptors in thalamocortical neurones.
Biochemical Pharmacology Lectures, 3rd year undergraduate BSc course.
Drugs and Drug Targets Tutorials
Student selected components dissertation supervisor of 1st year medical students
Herd, M.B., Lambert, J.J., Belelli, D. (2014) The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurones by modulating multiple modes of GABAA receptor-mediated inhibition. Eur J. Neurosci. (in press)
Maguire, E.P., Macpherson, T., Swinny, J., Dixon, C.I., Herd, M.B., Belelli, D., Stephens, D.N., King, S.L., Lambert JJ (2014). Tonic inhibition of accumbal spiny neurons by extrasynaptic ?4b? GABAA receptors modulates the actions of psychostimulants. J. Neurosci., 34(3) 823-838.
Herd, M.B., Brown, A.R., Lambert JJ, Belelli, D. (2013). Extrasynaptic GABAA receptors couple presynaptic activity to postsynaptic inhibition in the somatosensory thalamus.J. Neurosci.,33(37): 14850 – 68.
Wlodarczyk A., Sylantyev S., Herd, M.B., Kersant F., Lambert JJ Rusakov D, Linthorst, A., Semyanov A., Belelli D, Pavlov I, and Walker M. (2013). GABA-independent GABAA receptor openings maintain tonic currents.J Neurosci.33(9): 3905-3914.
Herd, M.B., Foister, N., Chandra, D., Peden, D.R., Homanics, G.E., Brown, V.J., Balfour, D.J.K., Lambert JJ, Belelli, D. (2009). Inhibition of thalamic excitability by THIP: a selective role for d-GABAA receptors. Eur. J. Neurosci., 29: 1177 – 1187.
Wafford, K.A., van Niel, M.B., Ma, Q.P., Horridge, E., Herd, M.B., Peden, D.R., Belelli, D., Lambert JJ (2009). Novel compounds selectively enhance ? subunit containing GABAA receptors and increase tonic currents in thalamus. Neuropharmacology, 56: 182 – 189.
Herd, M.B., Haythornthwaite, A.R., Rosahl, T.W., Wafford, K.A., Homanics, G.E., Lambert JJBelelli, D. (2008). The expression of GABAA b subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J. Physiol., 586.4, 989-1004.
Peden, D.R.*, Petitjean, C.M.*, Herd, M.B.*, Durakoglugil, M., Rosahl, T.W., Wafford, K., Homanics, G.E., Belelli, D., Fritschy, J.M., Lambert JJ (2008). Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurons. J. Physiol.586.4, 965-987.*equal contribution
Mitchell, E.A., Herd, M.B., Gunn, B.G., Lambert JJ, Belelli, D. (2008). Neurosteroid modulation of GABAA receptors: Molecular determinants and significance in health and disease. Neurochem. Int.,52: 588-595.
Herd MB, Belelli, D., Lambert JJ. (2007) Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharmacol Ther. 116(1):20-34.
Belelli, D, Herd MB, Mitchell EA, Peden DR, Vardy AW, Gentet L, Lambert JJ (2006) Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience 138: 821-829.
Borghese CM, Storustovu S, Ebert B, Herd MB, Belelli, D, Lambert JJ, Marshall G, Wafford KA, Harris RA (2006) The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol. J Pharmacol Exp Ther 316: 1360-1368.
Lambert JJ, Haythornthwaite A, Peden, DR, Herd, MB, Wafford, KA, Rosahl, TW, Belelli, D. (2005) The GABAA receptor: an important target for the general anaesthetic etomidate. International Congress Series, 1283, 67-72.
Belelli, D., Herd MB (2003) The contraceptive agent Provera enhances GABA(A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids? J Neurosci 23: 10013-10020.
Martin DJ, McClelland D, Herd MB, Sutton KG, Hall MD, Lee K, Pinnock RD, Scott, R H (2002). Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharm. 42, 353-366