AMPA-receptor trafficking and injury-induced cell death

Abstract

AMPA receptors (AMPARs) are critical for synaptic plasticity, and are subject to alterations based on subunit composition and receptor trafficking to and from the plasma membrane. One of the most potent regulators of AMPAR trafficking is the pro-inflammatory cytokine tumor necrosis factor (TNF)α, which is involved in physiological regulation of synaptic strength (Beattie et al., (2002) Science, 295, 2282-2285; Stellwagen and Malenka, (2006) Nature, 440, 1054-1059) and is also present at high concentrations after CNS injury. Here, we review evidence that TNF can rapidly alter the surface expression of AMPARs so that the proportion of Ca(++) -permeable receptors is increased and that this increase, in combination with increased levels of extracellular glutamate after injury, plays an important role in enhancing excitotoxic cell death after CNS injury. Thus, the pathophysiological hijacking of a critical regulator of synaptic plasticity and homeostasis by the secondary injury cascade may represent a new therapeutic target for neuroprotection.

Fig. 1

AMPAR trafficking to the synaptic membrane after spinal contusion injury. (A) Schematic representation of a horizontal section through the ventral horn of the spinal cord after unilateral contusion injury. Neurons were sampled in the lesion penumbra (dashed ellipse) just beyond the site of frank lesion. The contralateral side served as a control. (B) C-fos labeling in the lesion penumbra defined a region of interest for high-resolution confocal microscopy. (C and D) Spinal cord injury induced a marked increase in synaptic AMPAR levels relative to the contralateral uninjured tissue as revealed by laser scanning confocal microscopy coupled with 3-D blind deconvolution. (E) Automated image analysis revealed a significant increase in synaptic AMPAR puncta at 90 min and 3 h after injury, although the effect was more pronounced at the acute time point. *P < 0.05.

Fig. 2

Reduction in AMPAR trafficking and excitotoxicity following spinal cord injury after treatment with the TNF inhibitor soluble TNF receptor 1 (sTNFR1). (A) Representative confocal images depict the partial reversal of injury-induced increases in synaptic AMPAR levels. (B) Automated image analysis revealed a significant decrease in AMPAR puncta within the synaptic membrane. (C) Survival of neurons increased in the ventral gray matter as a function of distance from the lesion epicenter. (D) Automated cell counting algorithm revealed greater numbers of surviving large-diameter (> 40 μm) neurons within the a priori sample window within the lesion penumbra. (E) Quantitative comparisons revealed a significant increase in surviving neuron numbers in the sTNFR1 group relative to either injury alone or BSA vehicle treatment. *P < 0.05.