Professor Jeremy Lambert

Our research focuses on synaptic transmission

ie. how brain neurones communicate with one another. Understanding this neural conversation is essential to comprehending neurological conditions such as epilepsy, psychiatric disorders including anxiety, depression and schizophrenia and devastating diseases such as Alzheimer’s and Parkinson’s.

GABAA receptors and inhibitory neurotransmission

GABAA receptors are the major inhibitory receptors in the mammalian brain and an important site of action of many clinically important drugs used in the treatment of a variety of conditions including epilepsy, anxiety, insomnia and to induce anaesthesia during surgery. The human brain expresses 20-30

GABAAreceptor subtypes, however current therapeutics are non-selective and interact with many of these isoforms. Consequently, for such drugs the desired therapeutic effect, eg anxiolysis, is often associated with side effects (sedation, tolerance, addiction) that limits their clinical utility. Encouragingly, our research and that of others, reveals that distinct receptor subtypes influence different behaviours, for example different GABAA receptors mediate a) the anxiolytic, sedative and amnestic effects of diazepam. These findings may lead to the development of a new generation of therapeutics, but more fundamentally, given that these receptors exhibit distinct expression patterns in the brain, may permit an understanding of how neural activity influences behaviour in health and disease.

Neurosteroids: The brain's natural anxiolytic?

We and others have discovered that the brain can synthesize neurosteroids – which act to potently enhance GABAA receptor function and consequently "fine-tune" neuronal activity. Perturbations of neurosteroid levels are implicated in certain forms epilepsy, anxiety and depression and in mediating the behavioural effects of a variety of psychoactive drugs including ethanol. We are currently investigating what controls the sensitivity of different neurons to neurosteroids and the impact locally produced neurosteroids have on neuronal activity.

I am just going to put you to sleep: the mechanism of action of intravenous general anaesthetics:

Today it is hard to imagine undergoing major surgery without a general anaesthetic. Although they have been used clinically for over 160 years, the mechanism whereby general anaesthetics produce their characteristic rapid, but reversible loss of consciousness, has remained a medical mystery. Recently our work and that of others has identified particular subtypes of GABAAreceptor as an important targets for certain anaesthetics such as etomidate and propofol. We are currently focusing on where in the brain these receptors are located and how they influence neuronal communication. Such studies should permit a better understanding of the brain circuitry involved in sleep, sedation and unconsciousness and may in the future permit the development of a new generation of safer general anaesthetics.

Relating receptor structure to function

The "cys-loop" family of transmitter-gated ion channels includes nicotinic, 5HT3, glycine and GABAAreceptors. These proteins have evolved to permit the rapid transfer of information from one neurone to another. Upon binding of the neurotransmitter, such receptors respond within microseconds by changing their conformation to permit the flow of ions across the neuronal cell membrane. This ion translocation occurs via the second transmembrane (TM) crossing region of the protein. However, we have discovered that for 5HT3 nicotinic and glycine receptors that the large intracellular loop, (that connects TM3 to TM4), has a considerable influence on ion flow and selectivity. Indeed, this part of the protein appears to form portals, or windows, through which the ions must flow. These findings challenge the textbook view on how such receptors operate and suggest that this portion of the receptor protein may provide a new target for drug development.

The research laboratories at Ninewells Hospital & Medical School are run in collaboration with Dr. Belelli and Professor Peters and currently are staffed by 14 researchers. Additional internal collaborations are with Dr. Sutherland, Professor Schweiger, Professor Balfour, Dr. Rozov and Professor Hales.

Current research includes

• Neurosteroids: The brain’s natural valium?
• GABAA receptor subtypes mediate the actions of general anaesthetics.
• Development of novel anxiolytics and cognitive enhancing agents by targeting GABAA receptor subtypes.
• The role of GABAA receptor subtypes in addiction to cocaine.
• Pertubations of neurotransmission in Alzheimer’s and Huntington’ s disease.
• Relating the structure of nicotinic, serotonin and GABAA receptors to function.

Representative recent references

Dixon, C.L., Morris, H.V., Breen, G., Desrivieres, S., Jugurnauth, S., Steiner, R.C., Vallada, R., Guindalini, C., Lavanjeira, R., Messas, G., Rosahl, T.W., Atack, J.R., Peden, D.R., Belelli, D., Lambert, J.J., King, S.L., Schumann, G., Stephens, D.N. (2010). Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit – containing GABAA receptors. Proc. Natl. Acad. Sci. USA, 107:2289-2294.

Peters, J.A., Cooper, M.A., Carland, J.E., Livesey, M.R., Hales, T.G., Lambert, J.J. (2010). Novel structural determinants of single channel conductance and ion selectivity in 5-hydroxytryptamine-type3 and nicotinic acetylcholine receptors. J Physiol, 588.4:587-595.

Peters, J.A., Cooper, M.A., Livesey, M.R., Carland, J.E. & Lambert, J.J. (2010). 5-HT3 receptors, In: The Ion Channels. Ed. Kew, J. & Davies, C. Oxford University Press, (New York). Eds. Kew J. & Davies C. pp231-251.

Lambert, J.J., Cooper, M.A., Simmons, R.D., Weir, C.J., Belelli, D. (2009). Neurosteroids: Endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology, 34S: S48-58.

Herd, M.B., Foister, N., Chandra, D., Peden, D.R., Homanics, G.E., Brown, V.J., Balfour, D.J.K., Lambert, J.J., Belelli, D. (2009). Inhibition of thalamic excitability by THIP: a selective role for delta-GABAA receptors. Eur. J. Neurosci., 29(6): 1177-1187.

Wafford, K.A., van Niel, M.B., Ma, Q.P., Horridge, E., Herd, M.B., Peden, D.R., Belelli, D., Lambert, J.J. (2009). Novel compounds selectively enhance delta subunit containing GABAA receptors and increase tonic currents in thalamus. Neuropharmacology, 56: 182-189.

Carland, J.E., Cooper, M.A., Sugiharto, S., Jeong, H.J., Lewis, T.M., Barry, P.H., Peters, J.A., Lambert, J.J., Moorhouse, A.J. (2009). Characterization of the effects of charged residues in the intracellular loop on ion permeation in alpha1 glycine receptor – channels. J. Biol., Chem., 284: 2023 – 2030.

Livesey, M.R., Cooper, M.A., Deeb, T.Z., Carland, J.E., Kozuska, J., Hales, T.G., Lambert, J.J., Peters, J.A. (2008). Structural determinants of Ca2+ permeability and conduction in the human 5-HT3A receptor. J. Biol. Chem., 283, 19301-19313.

Ahrens, J., Leuwer, M., Stachura, S., Krampfl, K., Belelli, D., Lambert, J.J., Haeseler, G. (2008). A transmembrane residue influences the interaction of propofol with the strychnine-sensitive glycine alpha 1 and alpha 1 beta receptor. Anesthesia & Analgesia, 107: 1875 - 1883.

Herd, M.B., Haythornthwaite, A.R., Rosahl, T.W., Wafford, K.A., Homanics, G.E., Lambert, J.J., Belelli, D. (2008). The expression of GABAA 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, J.J. (2008). Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurons. J. Physiol. 586.4, 965-987.

Mitchell, E.A., Herd, M.B., Gunn, B.G., Lambert, J.J., Belelli, D. (2008). Neurosteroid modulation of GABAAreceptors: Molecular determinants and significance in health and disease. Neurochem. Int., 52, 588-595.

Herd, M.B., Belelli, D., Lambert, J.J. (2007). Neurosteroid modulation of synaptic and extrasynaptic GABAAreceptors. Pharmacology and Therapeutics, 116: 20-34.

Agid, Y., Buzsaki, G., Diamond, D.M., Frackowiak, R., Giedd, J., Girault, J.A., Grace, A., Lambert, J.J., Manji, H., Mayberg, H., Popoli, M., Prochiantz, A., Richter-Levin, G., Somogyi, P., Spedding, M., Svenningsson, P., Weinberger, D. (2007). How can drug discovery for psychiatric disorders be improved? Nat. Rev. Drug Discov., Mar 6(3), 189-201.

Deeb, T.Z., Carland, J.E., Cooper, M.A., Livesey, M.R., Lambert, J.J., Peters, J.A., Hales T.G. (2007). Dynamic modification of a mutant cytoplasmic cysteine residue modulates the conductance of the human 5-HT3A receptor. J. Biol. Chem., 282(9): 6172-82.

Hales, T.G., Dunlop, J.I., Deeb, T.Z., Carland, J.E., Kelley, S.P., Lambert, J.J., Peters, J.A. (2006). Common determinants of single channel conductance within the large cytoplasmic loop of 5-HT3 and alpha 4 beta 2 nicotinic acetylcholine receptors. J. Biol. Chem., 281(12), 8062-8071.

Belelli, D., Herd, M.B., Mitchell, E.A., Peden, D.R., Vardy, A.W., Gentet, L., Lambert, J.J. (2006). Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance. Neuroscience, 138, 821-829.

Key Past Publications

Belelli, D., Peden, D.R., Rosahl, T.W., Wafford, K.A., Lambert, J.J. (2005). Extra-synaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics. J. Neurosci., 25(50), 11513-11520.

Belelli, D. & Lambert, J.J. (2005). Neurosteroids: endogenous regulators of the GABAA receptor. Nature Reviews Neurosci. 6(7), 565-575.

Peters, J.A., Hales, T.G. & Lambert, J.J. (2005). Molecular determinants of single channel conductance and ion selectivity in the cys-loop transmitter-gated ion channels. Insights from the 5-HT3 receptor. Trends Pharmacol. Sci., 11, 587-594.

Caraiscos, V.B., Elliott, E.M., Kong, K., You-Ten, E., Cheng, V.Y., Belelli, D., Newell, J.G., Jackson, M.F., Lambert, J.J., Rosahl, T.W., Wafford, K.A., MacDonald, J.F., Orser, B.A. (2004). Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by 5 subunit-containing GABAA receptors. Proc. Natl. Acad. Sci. U.S.A. 101, 3662-3667.

Kelley, S.P., Dunlop, J.I., Kirkness, E.F., Lambert, J.J. & Peters, J.A. (2003). A cytoplasmic region determines single channel conductance in 5-HT3 receptors. Nature, 424, 321-324.

Reynolds, D.S., Rosahl, T.W., Cirone, J., O’Meara, G.F., Haythornthwaite, A., Newman, R.J., Myers, J., Sur, C., Howell, O., Rutter, R., Atack, J., Macaulay, A.J., Hadingham, K.L., Hutson, P.H., Belelli, D., Lambert, J.J., Dawson, G.R., McKernan, R., Whiting, P.J. & Wafford, K.A. (2003). Sedation and anaesthesia mediated by distinct GABAA receptor isoforms. J. Neurosci., 23(24), 8608-8617.