SCIENCE / THE BRAIN : Researchers Isolate Genetic Key to Memory, Learning
Researchers at La Jolla’s Salk Institute have found the gene for one of the most sought-after chemicals in the brain, a protein that plays a key role in early learning and memory.
That protein, called the glutamate receptor, is intimately involved in the transmission of signals from one brain cell to another and is thus crucial to normal functioning of the brain.
Inborn defects in the glutamate receptor can produce epilepsy, while brain injuries such as stroke and trauma can trigger malfunctions in the receptor that cause permanent brain damage. The isolation of the gene for the receptor, reported in today’s Nature, may make possible the design of new drugs to combat these medical problems and, in the longer term, may lead to drugs that enhance memory and learning.
“This discovery is extremely important,” said neurobiologist Charles F. Stevens of the Yale Medical School. It is the culmination of an intense race to isolate and identify the receptor, he said, and the beginning of a new race to develop ways to take advantage of the knowledge
“People are going to be working in their labs day and night to follow up on this,” Stevens said in a telephone interview.
Scientists have long recognized that there are four major receptor systems in the brain that are involved in the most rapid communications between cells. The receptors are all proteins that are embedded in the external membranes of the brain cells. When they bind to specific messenger molecules, they trigger chemical changes within the cell.
Two of the receptor systems, the so-called GABA and glycine receptors, are suppressive, shutting brain cells down so they don’t transmit a signal. Such systems are involved, for example, in blocking off pain and in modulating muscle movements.
The other two systems, the acetylcholinergic and glutamate receptors, are excitatory, stimulating a brain cell to send a message on to other brain cells, a process known as “firing.” They are crucial in learning and memory and in computational and recognition processes.
Scientists had previously isolated the genes that code for the other three types of receptors, but the gene for the glutamate receptors has proved elusive--presumably because this receptor’s structure is substantially different from that of the other receptors. The new discovery thus means that neurologists now have all four types of receptors available for study and potential manipulation.
There are at least half a dozen different types of glutamate receptors in the brain.
One type of glutamate receptor binds very tightly to a chemical called kainic acid. Defects in this type of receptor cause the convulsions that characterize epilepsy.
Neurobiologist Stephen Heinemann and his colleagues at Salk report today that they have isolated and cloned the gene for the glutamate receptor that binds to kainic acid. They have shown that when kainic acid binds to this receptor, the receptor opens a pore or gate that allows electrically charged calcium ions to enter the cell. That influx creates an electrical potential that stimulates the cell to send a message on to another cell.
Another type of glutamate receptor binds to a chemical called NMDA. This receptor triggers a strengthening of communication links between brain cells that is thought crucial to the storage of memories. The NMDA receptor is also the site where PCP, the street drug also known as “angel dust,” binds to the brain to stimulate hallucinations.
The NMDA receptor also plays a crucial role in brain damage when stroke or trauma occurs. When the oxygen supply to brain cells is cut off by such an event, glutamate leaks out of the cells. Acting through the NMDA receptor, that overabundance of glutamate causes the cell to fire repeatedly--to the point where the cell self-destructs.
Pharmaceutical companies are extremely interested in learning the structure of the glutamate receptors, according to Heinemann, because the knowledge should make possible the design of drugs that could interfere with the destructive processes by binding to the receptor without causing the cells to fire.
Heinemann said in a telephone interview that, with the knowledge they have gained about the structure of the kainic acid receptor gene, they are well along the way toward isolating the genes for the other glutamate receptors, including the NMDA receptor gene.
Heinemann and his colleagues isolated the kainic gene and the receptor from the brains of rats because those animals are relatively easy to work with. Previous studies with the other three classes of receptors have shown that the rat receptors are very similar to their human counterparts, Heinemann said, and that information gained from them is directly applicable to humans.
Two other groups of researchers involving scientists from Salk also report independently in today’s Nature that they have isolated the genes for other brain proteins that bind kainic acid. In both cases, however, the proteins they observed--one from chickens and one from frogs--are much smaller than that observed by Heinemann. And in neither case does the protein appear to have a role in communication among brain cells, because the proteins do not cause a pore to open in the cell membrane.
It is likely, Stevens said, that these two kainic-acid-binding proteins may be involved in previously unknown physiological reactions. But the simultaneous appearance of the three papers, he wrote in a commentary in Nature, suggests that “something about Southern California must be good for research on excitatory amino acids.”
HOW THE GLUTAMATE RECEPTOR WORKS The glutamate receptor, which is involved in the learning process and memory formation, allows brain cells to communicate by converting a chemical signal into an electrical signal. 1-When one brain cell or neuron is about to send a message to another, it releases a molecule of glutamate, an amino acid. 2-The glutamate molecule binds to the glutamate receptor on the second brain cell. 3-This opens a pore or gate that allows electrically charged calcium atoms to flow into the cell. 4-The change in the electrical charge within the second brain cell stimulates it to send a message on to the next neuron in line by releasing another glutamate molecule.
