Researchers are testing various modalities to reduce glutamate-induced excitotoxic neuronal injury after ischemic stroke. The investigators record the postsynaptic potential of cortical neurons under various conditions. The neurons are exposed to glutamate, which causes them to depolarize; excessive depolarization triggers cell death. The experiment is repeated after altering the electrolyte composition of the extracellular fluid. When the extracellular magnesium concentration is increased, glutamate-induced neuron depolarization and cell death are decreased. Which of the following changes in ion conductance explains the improved neuron survival in response to magnesium?

Question

Researchers are testing various modalities to reduce glutamate-induced excitotoxic neuronal injury after ischemic stroke.  The investigators record the postsynaptic potential of cortical neurons under various conditions.  The neurons are exposed to glutamate, which causes them to depolarize; excessive depolarization triggers cell death.  The experiment is repeated after altering the electrolyte composition of the extracellular fluid.  When the extracellular magnesium concentration is increased, glutamate-induced neuron depolarization and cell death are decreased.  Which of the following changes in ion conductance explains the improved neuron survival in response to magnesium?

Quizplus · Accepted Answer

11ec160b_3cd1_b371_9249_5bea4cab5590_MD0001_00 Glutamate is the primary excitatory neurotransmitter in the brain. The glutamate NMDA receptor is a potential-dependent and ligand-gated ion channel. In the resting hyperpolarized state, magnesium occupies the NMDA receptor ion pore, forming a constitutive magnesium plug to prevent the flow of other cations. The channel opens when 2 events occur: Displacement of the magnesium plug: An initial depolarization impulse (non-NMDA mediated) causes loss of negative potential, displacing magnesium from the NMDA ion channel pore. In dying neurons, this can occur due to loss of the ATP-dependent sodium-potassium gradient. Binding of glutamate: After magnesium is expelled, binding of glutamate (along with glycine) induces a conformational change, allowing the unrestricted flow of calcium, sodium, and potassium. Because of selective permeability, the influx of calcium and sodium (tends to depolarize) outstrips the efflux of potassium (tends to hyperpolarize), leading to further net depolarization. Therefore, higher extracellular magnesium levels block the NMDA channel, decreasing the influx of calcium and sodium (Choice C) to inhibit glutamate-mediated neuron depolarization. During acute ischemic stroke, a sudden, massive rise in extracellular glutamate occurs within the infarct zone. Sustained exposure to high glutamate levels causes intracellular calcium overload, ultimately accumulating in mitochondria, triggering apoptotic neuron death (excitotoxicity). These dying neurons release more glutamate into the extracellular space, creating a domino effect on neighboring neurons, further propagating damage beyond the original ischemic core. As a result, modulation of the NMDA receptor is an emerging frontier in neuroprotection. (Choices B and D) The influx of chloride and bicarbonate anions induces hyperpolarization instead of depolarization, and mediates the inhibitory postsynaptic potentials generated by GABA-A channels; NMDA channels are impermeable to anions. Neurons can also be hyperpolarized by potassium efflux, mediating inhibitory potentials generated by GABA-B channels. (Choice E) Magnesium itself does not pass through the NMDA channel. Rather, it regulates passage of other cations through steric hindrance (magnesium plug). Therefore, magnesium is used therapeutically to block depolarization. Educational objective: Excessive activation of the glutamate NMDA receptor causes excitotoxic neuronal death through uncontrolled calcium influx. At the hyperpolarized resting membrane potential, the NMDA receptor is blocked by a magnesium plug, which is released by non-NMDA-mediated depolarization.

Researchers Are Testing Various Modalities to Reduce Glutamate-Induced Excitotoxic Neuronal