Glutamate, NMDA, and AMPA induced changes in extracellular space volume and tortuosity in the rat spinal cord

Glutamate release, particularly in pathologic conditions, may result in cel lular swelling. The authors studied the effects of glutamate, N-methyl-D-as partate (NMDA), and alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic ac id (AMPA) on extracellular pH (pH(e)), extracellular potassium concentratio n ([K+](e)). and changes in extracellular space (ECS) diffusion parameters (volume fraction a, tortuosity lambda) resulting from cellular swelling. In the isolated spinal cord of 4- to 12-day-old rats, the application of glut amate receptor agonists induced an increase in [K+](e), alkaline-acid shift s, a substantial decrease in oc, and an increase in lambda. After washout o f the glutamate receptor agonists, alpha either returned to or overshot nor mal values, whereas lambda remained elevated. Pretreatment with 20 mmol/L M g++, MK801, or CNQX blocked the changes in diffusion parameters, [K+](e) an d pH(e) evoked by NMDA or AMPA. However, the changes in diffusion parameter s 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 re lease may produce a large, sustained and [Ca2+](e)(-) dependent decrease in a and increase in lambda. Repetitive stimulation and pathologic states res ulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotox icity and neuronal damage.