The NMDA receptor is known to play a crucial role in memory, and synaptic plasticity - where neurons change, altering networks through use or disuse. NMDA receptors can be found at many excitatory synapses in the brain; they can allow sodium and calcium ions to move into neurons, and they are activated by glutamate, an excitatory neurotransmitter. As nerve signals are propagated, one neuron releases glutamate, which is taken up by another at the synapse.
During disease, however, this glutamate uptake is disrupted, and glutamate levels at the synapse become elevated. NMDA receptors outside of the synapse can then be activated by this excess glutamate. That can ultimately lead to neuronal damage or death, which can disrupt brain function. It's thought that excess glutamate outside of the synapses is a part of circulatory and neurodegenerative dysfunction; NMDA receptors that are not at the synapse and are activated by glutamate can have a destructive impact.
"The evidence suggests that the toxic properties of extrasynaptic NMDA receptors play a central role in a number of neurodegenerative diseases," explained Dr. Hilmar Bading, a Professor at the University of Heidelberg. Bading noted that it's a feature of both Alzheimer's disease and amyotrophic lateral sclerosis (ALS), and may also be linked to the brain damage that is sometimes seen after parasitic or viral infections.
"Understanding why extrasynaptic NMDA receptors lead to nerve cell death is the key to developing neuroprotective therapies," noted Bading.
Researchers used a mouse model to show that along with another ion channel, extrasynaptic NMDA receptors generate a kind of 'death complex.'
The other ion channel, TRPM4, has various functions throughout the body; it also functions in cardiovascular and immune responses. Data suggested that TRPM4 promotes the toxicity of NMDA receptors outside the synapse.
In new work reported in Science, researchers found the surfaces where the two channels make contact, and then looked for molecules that could disrupt this interaction, and inactivate the death complex. The investigators called these molecules "interface inhibitors," and they are thought to be neuroprotective; they may help prevent neurodegeneration by preventing extrasynaptic NMDA and TRPM4 receptors from interacting.
"We're working with a completely new principle for therapeutic agents here. The interface inhibitors give us a tool that can selectively remove the toxic properties of extrasynaptic NMDA receptors," said Bading.
The researchers have already used a mouse model of stroke and retinal degeneration to show that these inhibitors have therapeutic potential. They may one day become treatments for neurodegenerative disorders, many of which currently have none.
"However, their possible approval as pharmaceutical drugs for human use will take several more years because the new substances must first successfully pass through a number of preclinical and clinical testing phases," concluded Bading.