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Sensory Neurotransmitter Research

Background
One of the remarkable features of the brain is how the millions of cells in the brain communicate specific messages to each other and how these messages are interpreted and acted upon by recipient cells. For example, the human optic nerve, has about a million individual nerve fibres (or axons) carrying information from the retina in the eye to the various parts of the brain where the visual information is received and processed. The transfer of information from the terminals of the nerve fibre onto the recipient cells occurs via the release of chemical messenger molecules (called neurotransmitters) from the terminal: these molecules diffuse across a small gap (called the synapse) and lock onto specific sites (called receptors) on the target cell (Figure 1).

Optic nerve fibre terminal

What are the ingredients?

L-glutamic acid and L-aspartic acid
There are many dozens of different neurotransmitter chemicals in the brain, and probably more which remain to be discovered. The identification of these has been the subject of work from hundreds of laboratories around the world over many years. Some of these transmitters are complex peptides, others are simple ubiquitous molecules. For example, the amino acid L-glutamate, which is found throughout the body and in many foods is thought to be widely used in the brain as a transmitter. Some nerve cells can release several different transmitters, and these are thus present in the extracellular fluid, together with ions and other chemicals to form a complex 'soup'.

For a nerve cell (or neurone), the key to making sense of this mixture of transmitters and other materials is the receptor, which is embedded across the cell membrane. The specific interaction of the transmitter with the receptor, much like a key fitting into a lock, triggers a cascade of chemical and electrical events within the cell. The precise nature of these postsynaptic changes depends on the properties of the receptor. Thus one transmitter acting on different receptors, or a combination of transmitters acting on several different types of receptor can signal different types of information.

What's Cooking in the Lab?
The work of Professor Tom Salt's research group is to elucidate the transmitter–receptor interactions which underlie the transmission and processing of visual and other sensory information within the brain.

One of the ways in which this can be done is by recording the electrical activity of single cells from regions of the brain which receive input from the eye and other sensory systems. Applying small amounts of transmitters and chemically-related compounds in the vicinity of these cells whilst recording their activity enables us to compare the responses of these cells to their normal input with the responses to the compounds which we apply. This allows us to draw conclusions about the nature of the chemical transmission process. We are carrying this out in various sensory-recipient parts of the brain, and also investigating how these processes change during development and growth of the brain.

A particular focus of activity of this group has been the role of L-glutamate and its receptors in transmission. A variety of these receptors exist, each having distinct characteristics (see Figure 2 for more details of glutamate receptors). This enables the transmission of information within different time frames, from only several milliseconds to many minutes and beyond. Thus, for example, the release of L-glutamate from the terminal of an optic nerve fibre onto target cells in the brain can signal the start and end of a brief flash of light, leading to rapid electrical responses in the target cell. However, this release can also set in motion a complex cascade of intracellular events which can invoke long-term changes in the structure and function of the target cell.

In collaboration with colleagues at the Brain Research Institute of Zurich University we have developed a unique method which allows us to record the activity of brain cells while measuring the release of transmitter chemicals from the brain. This allows us to correlate the electrical activity with the release of chemicals from cells in the brain.

Glutamate receptors

Where is this leading? (What may be on the menu?)
We are building up a complex picture of how the various transmitters which are present in sensory structures of the brain are used under normal physiological conditions to signal visual and other sensory information, and how this function may in turn be modified by other transmitters. This fundamental understanding of how the system works is essential as a basis to understanding the processes which may occur in disease and injury. For example, it is now known that some neurodegenerative conditions and injury responses in the brain involve changes in glutamate metabolism, and the effects of these are mediated via glutamate receptors. Thus, the use of drugs which block the action of glutamate selectively at some of its receptors could be hypothesised to counteract some of these pathological responses, thereby reducing cell damage and degeneration.

It is known that as the brain develops and grows that specific nerve connections are made and maintained whilst other connections are lost: this depends on the neurotransmitter actions at the appropriate synapses. Some of the glutamate receptors (The so-called NMDA receptors and metabotropic receptors - see Figure 2) are implicated in these plastic phenomena, and we have been investigating how their function changes and how it may be modified by visual experience. This promises to reveal the conditions under which plasticity in the visual pathway can be maintained or even induced: this would open up the possibility whereby modulation of "molecular switches" with specific drugs could allow or facilitate the regeneration of damaged pathways.

Thus the study of fundamental biological and chemical processes in the brain lays the foundations for future potential treatments of neurological disorders.

For more detailed information, visit Tom Salt's Home Page

Selected Publications

Salt TE (2002) Glutamate receptor functions in sensory relay in the thalamus. Philosophical Transactions of The Royal Society B 357: 1759-1766.

Pothecary CA, Jane DE, Salt TE (2002) Reduction of excitatory transmission in the retino-collicular pathway via selective activation of mGlu8 receptors by DCPG. Neuropharmacology 43: 231-234.

Do KQ, Grima G, Benz B, Salt TE (2002) Glial-Neuronal Transfer of Arginine and S-Nitrosothiols in Nitric Oxide Transmission. Ann NY Acad Sci 962: 81-92.

Cirone J, Pothecary CA, Turner JP, Salt TE (2002) Group I metabotropic glutamate receptors (mGluRs) modulate visual responses in the superficial superior colliculus of the rat. Journal of Physiology 541:895-903.

Cirone J, Sharp C, Jeffery G, Salt TE (2002) Distribution of metabotropic glutamate receptors in the superior colliculus of the adult rat, ferret and cat. Neuroscience 109:779-786.

Salt TE (2001) Metabotropic glutamate (mGlu) receptors and nociceptive processing. Drug Development Research, 54:129-139.

Spooren WPJM; Gasparini F; Salt TE; Kuhn R; (2001) Novel allosteric antagonists shed light on mGluR5 receptors and CNS disorders. Trends in Pharmacological Sciences, 22: 331-337.

Cirone J; Salt TE; (2001) Group II and III metabotropic glutamate (mGlu) receptors contribute to different aspects of visual response processing in the superior colliculus. Journal of Physiology, 534: 169-178.

Binns KE; Salt TE; (2001) Actions of the systemically active metabotropic glutamate antagonist MPEP on sensory responses of thalamic neurones. Neuropharmacology, 40: 639-644.

Salt TE; Zhang H; Mayer B; Benz B; Binns KE; Do KQ; (2000) Novel mode of nitric oxide neurotransmission mediated via S-nitroso-cysteinyl-glycine. European Journal of Neuroscience, 12: 3919-3925.

Turner JP; Salt TE; (2000) Synaptic activation of the Group I metabotropic glutamate receptor mGlu1 on the thalamocortical neurons of the rat dorsal lateral geniculate nucleus in vitro. Neuroscience, 100: 495-507.

Salt TE; Binns KE; (2000) Contributions of mGlu1 and mGlu5 receptors to interactions with N-methyl-D-aspartate receptor-mediated responses and nociceptive sensory responses of rat thalamic neurones. Neuroscience, 100: 375-380.

Binns KE; Salt TE; (2000) The functional influence of nicotinic cholinergic receptors on the visual responses of neurones in the superficial superior colliculus. Visual Neuroscience, 17: 283-289.

Cirone J; Salt TE; (2000) Physiological role of group III metabotropic glutamate receptors in visually responsive neurons of the superficial superior colliculus. European Journal of Neuroscience, 12: 847-855.

Turner JP; Salt TE; (1999) Group III metabotropic glutamate receptors control corticothalamic synaptic transmission in the thalamus in vitro. Journal of Physiology, 519: 481-491.

Salt TE; Turner JP; Kingston AE; (1999) Evaluation of agonists and antagonists acting at Group I metabotropic glutamate receptors in the thalamus in vivo. Neuropharmacology, 38: 1505-1510.

Salt TE; Binns KE; Turner JP; Gasparini F, and Kuhn R (1999) Antagonism of the mGlu5 agonist 2-chloro-5-hydroxyphenylglycine by the novel selective mGlu5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) in the thalamus. British Journal of Pharmacology, 127: 1057-1059.

Shaw PJ; Charles SL; Salt TE; (1999) Actions of 8-Bromo-cyclic-GMP on neurones in the thalamus in vivo and in vitro. Brain Research, 833: 272-277

Binns KE; Turner JP; Salt TE; (1999) Visual experience alters the molecular profile of NMDA-receptor-mediated sensory transmission. European Journal of Neuroscience, 11: 1101 -1104

Binns KE; Salt TE; (1998) Experience-dependent changes in the importance of N-methyl-D- aspartate (NMDA) receptors for visual transmission in superior colliculus. Developmental Brain Research, 110: 241-248

Turner JP; Salt TE; (1998) Characterization of sensory and corticothalamic excitatory inputs to thalamocortical neurones in vitro. Journal of Physiology, 510: 829-843

Salt TE; Turner JP; (1998) Modulation of sensory inhibition in the ventrobasal thalamus via activation of Group II metabotropic glutamate receptors (mGluRs) by 2R,4R-APDC. Experimental Brain Research, 121: 181-185

Salt TE; Turner JP; (1998) Reduction of sensory and metabotropic glutamate receptor responses in the thalamus by the novel mGluR1-selective antagonist S-2-methyl-4-carboxy-phenylglycine (LY367385). Neuroscience, 85:655-658

Binns KE; Salt TE; (1998) Developmental changes in NMDA receptor mediated visual activity in the superior colliculus. Experimental Brain Research, 120: 335-344

Binns KE; Salt TE; (1997) Different roles for GABAA and GABAB receptors in visual processing in the superior colliculus. Journal of Physiology, 504: 629-639

Shaw PJ; Salt TE; (1997) Modulation of sensory and excitatory amino acid responses by nitric oxide donors and glutathione in the ventrobasal thalamus. European Journal of Neuroscience, 9: 1507-1513

Binns KE; Salt TE; (1997) Post eye-opening maturation of visual receptive field diameters in the superior colliculus. Developmental Brain Research, 99: 263-266.

Jeffery G; Sharp C; Malitschek B; Salt TE; Kuhn R; Knopfel T; (1996) Cellular localisation of metabotropic glutamate receptors in the optic nerve: A mechanism for axon-glia communication. Brain Research, 741: 75-81.

Salt TE; Eaton SA; Turner JP; (1996) Characterisation of the metabotropic glutamate receptors (mGluRs) which modulate GABA-mediated inhibition in the ventrobasal thalamus. Neurochemistry International, 29: 317-322.

Do KQ; Benz B; Grima G; GutteckAmsler U; Kluge I; Salt TE; (1996) Nitric oxide precursor arginine and S-nitrosoglutathione in synaptic and glial function. Neurochemistry International, 29: 213-224.

Binns KE; Salt TE; (1996) Corticofugal influences on visual responses in superior colliculus: The role of NMDA receptors. Visual Neuroscience, 13:683-694.

Eaton SA; Salt TE; (1996) Role of NMDA and metabotropic glutamate receptors in cortico-thalamic excitatory post-synaptic potentials in vivo. Neuroscience, 73:1-5.

Salt TE; Eaton SA; (1996) Functions of ionotropic and metabotropic glutamate receptors in sensory transmission in the thalamus. Progress in Neurobiology, 48:55-72.

Binns KE; Salt TE; (1996) The importance of NMDA receptors for multi-modal integration in the deep layers of the superior colliculus. Journal of Neurophysiology, 75:920-930.

This page last modified 4 April, 2006 by David Daniel


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