Glutamate, NMDA, and AMPA Induced Changes in Extracellular Space Volume and Tortuosity in the Rat Spinal Cord

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Abstract
Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-d-aspartate (NMDA), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pHe), extracellular potassium concentration ([K+]e), and changes in extracellular space (ECS) diffusion parameters (volume fraction α, tortuosity λ) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K+]e, alkaline-acid shifts, a substantial decrease in α, and an increase in λ. After washout of the glutamate receptor agonists, α either returned to or overshot normal values, whereas λ remained elevated. Pretreatment with 20 mmol/L Mg++, MK801, or CNQX blocked the changes in diffusion parameters, [K+]e and pHe evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca2+-free solution, which had no effect on the [K+]e increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca2+]e-dependent decrease in α and increase in λ. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.