Excitotoxicity · Grey Matter

Excitotoxicity is the death of neurons caused by too much excitation, above all by glutamate that keeps its receptors open too long, and it is a common final path of damage in stroke, brain injury and prolonged seizures.

Excitotoxicity. Excitotoxicity is the death of neurons caused by too much excitation, above all by glutamate that keeps its receptors open too long, and it is a common final path of damage in stroke, brain injury and prolonged seizures.

The term was coined by John Olney in 1969, after he found that large doses of glutamate destroyed neurons in young mice. The damage comes in two parts. First, sodium and chloride pour in through open glutamate receptors and water follows, so neurons swell within minutes. Second, and decisive, calcium enters through NMDA receptors and voltage-gated calcium channels and overwhelms the cell's buffers. The excess calcium activates proteases (calpains), lipases and nitric oxide synthase, loads the mitochondria until they fail and release cytochrome c, and produces reactive oxygen species; the cell dies by necrosis or by triggered programmes over the following hours.

It feeds on itself. Dying and depolarised neurons release more glutamate, and when astrocytes lack the energy to run their transporters, or even run them backwards, glutamate accumulates further.

Energy failure is the usual cause. In ischaemia the ischaemic cascade links missing ATP to glutamate release, which is why the zone around a stroke is at risk for hours.

Blocking it has been hard. NMDA antagonists protect neurons in animal models but failed in clinical trials for stroke, partly because the same receptors are needed for normal function and because treatment usually comes too late.

The signal that drives learning becomes the poison when energy runs out.

Calcium through NMDA receptors is the message of plasticity in small doses and a trigger of cell death in large, sustained ones.

Questions: Does a long seizure burn the brain with its electricity? The currents of a seizure are those of ordinary firing neurons and do not heat or burn the tissue. When damage happens, it is metabolic and chemical. Neurons driven to fire for many minutes release glutamate continuously, calcium floods in through NMDA and other receptors, and the calcium switches on enzymes that break down membranes, the cytoskeleton and DNA, a process called excitotoxicity. Energy demand outruns supply, mitochondria are strained, free radicals accumulate and cells swell. This is why status epilepticus has a time point, about 30 minutes for convulsive seizures, after which neuronal death becomes likely, while a brief seizure usually leaves no detectable damage. How does too much glutamate kill a neuron? When glutamate stays high, its receptors stay open: sodium, chloride and water rush in and neurons swell within minutes, and calcium floods in through NMDA receptors and voltage-gated calcium channels. Experiments in cultured neurons showed that removing sodium prevents the swelling but the cells still die later unless calcium is removed too, so calcium is the lethal part. The excess calcium activates proteases and lipases, drives nitric oxide synthase, and overloads the mitochondria until they fail and release signals for cell death, producing reactive oxygen species on the way. Olney named the process excitotoxicity in 1969, and it is the shared final step of damage in stroke, trauma and prolonged seizures. Why does a lack of energy turn into a flood of glutamate? Glutamate is cleared by transporters that use the sodium gradient, and that gradient is kept by the ATP-driven pump. When ATP fails, the gradient runs down and the transporters slow, stop, and can even run in reverse, releasing glutamate from astrocytes and neurons. At the same time depolarised terminals open their calcium channels and release vesicles, adding more. The glutamate depolarises the neighbouring cells, which worsens their own energy deficit, so energy failure and excitation feed each other in a loop that spreads through tissue short of blood.