Killing Neurons with Excitement

We know that much of the damage from strokes comes from an overload of glutamate, an excitatory neurotransmitter. Neurodegenerative changes in Alzheimer's Disease is probably also due to glutamate overexcitation, at least in part. Now scientists are beginning to tease apart the mechanism of excitative neurotoxicity. This news release give more information:

For neurons, overexcitement is deadly. To avoid this, brain cells must sop up unneeded neurotransmitters from the synapse through membrane-bound transporters. If these transporters fail, neurons and other brain cells get excited to death-- a phenomenon that may contribute to brain damage during stroke and Alzheimer's disease.

Indeed, brain deterioration after stroke is associated with elevated levels of glutamate -- the major excitatory neurotransmitter in the mammalian central nervous system (CNS) -- in the plasma and cerebral spinal fluid. One possible explanation for this glutamate build-up, reported online on March 6th in The Journal of Experimental Medicine, is a mutation in the gene encoding the glutamate transporter protein EAAT2.

This mutation --- a single nucleotide change in the promoter region of the EAAT2 gene -- was equally prevalent in healthy individuals and stroke patients. But among stroke patients, those with the mutated allele had higher plasma levels of glutamate and were more likely to suffer from post-stroke neurological problems than those with the normal allele.

The mutation changed a binding site for the activating transcription factor AP-2 into a binding site for the repressor GCF2 -- a swap that inhibited promoter activity in transfected rat brain cells. Whether the mutant promoter decreases EAAT2 expression in the human brain, as would be predicted, remains to be tested.

Little by little, gene by gene, protein by protein, science is learning why humans suffer the way they do. And little by little science is finding ways to do something about it.