MAKING SENSE OF THE SOUP

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).

What are the ingredients?

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 located 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 postsynapticchanges 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 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.

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 neuro-degenerative 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.

This page was written by Tom Salt, and is part of the Neurotransmitters in Sensory Systems Home Page.