LONDON -- A protein found in nerve cells in the mammalian brain plays a key role in helping to control the processes of learning and memory, new research has shown. Transgenic mice that lack the protein, which is called postsynaptic density-95 (PSD-95), have a severe learning impairment.
The work could lead to novel drug targets for conditions such as Alzheimer's disease and stroke, as well as to the development of treatments for the learning impairments that occur in normal aging and in some children, the researchers predict. Martine Migaud and colleagues based in Edinburgh, U.K., Los Angeles and New York describe their study in a paper in the current issue of Nature titled "Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein."
Seth Grant, senior author of the paper, told BioWorld International the researchers have "shown that the gene for PSD-95 is crucial to the way nerve cells respond to activity. It appears to be particularly important in controlling the way nerve cells communicate with one another."
During nervous activity in the brain, nerve impulses called action potentials pass from one nerve cell to the next, across connections called synapses. When an animal is experiencing an event that it will ultimately learn, the nerve cells in its brain have an altered firing pattern, which then leads to changes in the efficiency of synapses. In this way, learning can modify brain circuits.
According to current theories, memories result when these changes are long-lasting. A long-lasting increase in synaptic efficiency is called long-term potentiation, while a long-term decrease in synaptic efficiency is called long-term depression.
PSD-95 is a protein found at postsynaptic sites in nerve cells. It can bind to N-methyl-D-aspartate (NMDA) receptors, which are also found at synapses. Earlier studies of the role of PSD-95 had indicated that it might be important in holding NMDA receptors in the synapse.
Grant, director of the Centre for Neuroscience at the University of Edinburgh, with his long-term collaborator Thomas O'Dell, of the department of physiology and the Brain Research Institute at the School of Medicine, in the University of California at Los Angeles, and their collaborators, decided to examine the function of PSD-95 further. They carried out a gene-targeting experiment that introduced a mutation in the gene for PSD-95.
Grant explained: "In the mice which had the PSD-95 gene mutated, we found that the NMDA receptor was present at synapses as normal -- which raises a bit of a challenge to the existing hypothesis." The researchers also carried out electrophysiological studies on slices of the hippocampus (a part of the brain which plays an important role in storage of memories) from the mutant mice.
Their experiments showed that, when they gave particular types of stimulation to the synapses, which in normal mice produce a small increase in potentiation (efficiency of transmission), this was not the case in the PSD-95 mutant mice. "We got this super-potentiation," Grant said. "It appears that, when you don't have PSD-95, the synapses become overly efficient, or too greatly potentiated. We think this is because PSD-95 binds to other proteins, and when PSD-95 is missing, so are the other proteins. When they are missing, you get too much potentiation, and this tells us that these proteins are negative regulators -- their job normally is to restrain potentiation, like a brake on the system."
In addition, Grant, O'Dell and their colleagues presented the homozygous mutant mice with a learning task. When the mice were put into a water maze, in which they have to remember the position of a hidden platform under the water according to visual cues, it was clear that they had a profound learning impairment. "This was really very striking," Grant said. "It was also surprising -- some of us had speculated that they would be super-learners. But they weren't. They are severely impaired in their ability to learn."
So, what do these results suggest about the role of PSD-95? "These studies indicate that unless you have a synapse very finely tuned, such that during learning it only becomes potentiated a certain amount -- not too much, not too little -- then under those circumstances you get optimal encoding and storage of information in your brain," Grant said. "PSD-95 is a key molecule in controlling those processes."
Commenting on the paper in a "News and Views" article in the same issue of Nature, Robert Malenka, of the departments of psychiatry and physiology, and Roger A. Nicoll, of the departments of cellular and molecular physiology and physiology, both at the University of California, San Francisco, write: "Migaud and colleagues elegantly show that we now have the tools to understand the molecular architecture of excitatory synapses in the mammalian brain. Their study also emphasizes the surprises that are in store as we try to work out how a specific protein embedded in this complex architecture leads to synaptic function and, eventually, to behaviour."
Grant's long-term aim is to continue to analyze the different roles of the various proteins involved in the transmission of nervous impulses in the brain, with the help of targeted mutations. He predicted that, in several years, a detailed biochemical pathway of the molecules involved in learning and memory will be available, analogous to those available for metabolism in general.
He also suggested that the identification of the roles of molecules such as PSD-95 could lead to a new class of cognition-enhancing drugs in people with neurodegenerative diseases such as Alzheimer's disease. It may even be possible to develop therapies to combat the effects of normal aging, he added.
In addition, Grant said, the discovery may lead to new treatments for people who have suffered strokes. "During a stroke," he said, "too much of the neurotransmitter glutamate is released into the synapses, and this overactivates the NMDA receptors, with the result that the cells die. If you could block the NMDA receptors when someone has a stroke, you could limit the amount of damage to the brain. But, by the time most people get to hospital, it is too late. What we really need is drugs which work on the biochemical pathways that are downstream from the NMDA receptor, those that are activated minutes to hours after the stroke begins. PSD-95 appears to be in this category, because it appears to regulate the NMDA receptor signaling in about the first half hour after the activation of the NMDA receptor. So, it is possible that it could be used to control this type of neuronal damage." *