Developmental changes in NMDA-induced cell swelling and its transition to necrosis measured with 1H magnetic resonance imaging, impedance and histology

Abstract

The vulnerability of the rat brain to intracerebrally injected N-methyl- d-aspartate (NMDA) drastically changes with age. We evaluated the developmental changes in the early and late responses to NMDA using 1H magnetic resonance imaging (MRI), cortical impedance and histology. NMDA, injected in the striatum of rats at postnatal days (P) 4, 7, 10, 14 and 21, induced a significant age-dependent reduction in the apparent diffusion coefficient (ADC) of tissue water in the striatum and the cerebral cortex monitored 1 h later using diffusion-weighted MRI. The reduction in ADC amounted 65% at P4 with lower values thereafter and was about 30% at P21. NMDA similarly induced a reduction in the cortical extracellular space (by 50% at P7 and 10% at P16) as measured with impedance recordings. The progressive decrease in the effect of NMDA with brain development was also indicated by a decrease in the volume of tissue in which the changes in ADC occurred (50 mm 3 at P4 and 8 mm 3 at P21). The diffusion of extracellular tracer molecules Mn 2+ or [ 3]H-( R)-α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) injected in the striatum and monitored with T 1-weighted MRI and autoradiography respectively showed a similar age dependence with the diffusion volume being twofold larger in P7 than in P21 brain. Thus restriction in diffusion during brain development may contribute to the decrease in NMDA-induced injury with age. The volume of tissue necrosis and gliosis, measured with T 2-weighted MRI and histology 5 days after NMDA injection, was similar to that outlined by the ADC reduction detected soon after the insult at P4, P7 and P21. However, at P10 and P14 only 50% of the tissue showing a hyperintense signal in DW images displayed necrosis and gliosis 5 days later. This study shows that during development the early response to NMDA in terms of cytotoxic cell swelling (indicated both with impedance recordings and diffusion-weighted MRI) decreases with age. In addition, with maturation only part of the brain tissue acutely affected by NMDA does proceed into necrosis and gliosis, indicating an increased capacity of cells in the developing rat brain to survive NMDA-induced cell swelling.