A Brain Receptor's Stroke of Fate

As a young brain develops, or as an older one learns new tricks, some connections between neurons flourish while others fade away. This crucial tuning is guided by the so-called NMDA receptor. But this same receptor unleashes deadly havoc during a stroke. A new study explains why: These Jekyll and Hyde-like properties depend on the receptor's location on nerve cells--a finding that could help the fight against brain damage resulting from stroke.

One prominent feature of nerve communication is the spread of glutamate from one neuron to another. After this neurotransmitter crosses the gap--called a synapse--it stimulates receptors that pass the signal along. Yet at the same time, NMDA receptors are shaping the communication. They help nerve cells fiddle with the sensitivity of the synapse, a process known as synaptic plasticity. On a broader scale, NMDA receptors coordinate the construction of new synapses and the survival of nerve cells in the developing nervous system. Paradoxically, NMDA receptors can also convey the kiss of death: During a stroke, glutamate leaks from distressed brain cells and binds to NMDA receptors, triggering the neurons to kill themselves. That in turn leads to irreversible brain damage.

Neurobiologist Hilmar Bading at the Medical Research Council lab in Cambridge, U.K., and colleagues now suggest that this variability depends on the NMDA receptor's location on a nerve cell. In a study of cultivated rat brain cells, published online by Nature Neuroscience on 15 April, the team showed that NMDA receptors sitting in synapses turn on a signaling pathway leading to the activation of CREB, a protein that promotes a neuron's survival. NMDA receptors positioned anywhere else on the cell shut down CREB, killing the neuron. By designing drugs to target a subunit that is unique to NMDA receptors outside the synapse, researchers one day may be able to limit brain damage after a stroke without interfering with neuronal communication, the team says.

Dennis Choi, vice president for neurosciences at Merck Research Laboratories in West Point, Pennsylvania, and an expert on glutamate's toxic effects on the brain, says the idea that NMDA receptors may have different effects depending on their location is an interesting hypothesis--but one that needs to be confirmed. "If it turns out to be correct, it will trigger a lot of new experiments and new thoughts about how we approach glutamate toxicity," Choi says.

Related sites
Hilmar Bading's home page
The CREB pathway