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Expression of NMDA receptor mRNAs in rat motoneurons is down-regulated after axotomy
1Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Abstract:
The cytotoxic effects of glutamate via the N-methyl-D-aspartate (NMDA) receptor have been suggested to take part in the events leading to death of motoneurons after neonatal axotomy. By the use of in situ hybridization and immunohistochemistry we have investigated motoneuron mRNA expression of the NMDA receptor subunits NR1, NR2B and NR2D and of the NR1 subunit protein in two lesion models leading to partial motoneuron death: sciatic nerve transection early postnatally in the rat and ventral root avulsion in the adult rat. The results were compared with a lesion model with no subsequent death of motoneurons, i.e. sciatic nerve transection in the adult rat. All lesions were followed by down-regulation of the mRNAs for all studied subunits in severed motoneuron populations; down-regulation was detectable already at early stages postoperatively before any significant death had taken place. The strongest down-regulation was in fact seen in the lesion with the largest loss of motoneurons (ventral root avulsion). The reduction in the expression of NR1 mRNA was paralleled by a decrease in NR1 subunit protein. We conclude that down-regulation of NMDA receptor subunit expression is part of the acute response to axonal injury in motoneurons, whether or not neuronal death follows, and that the susceptibility of lesioned motoneurons to excitotoxic effects should be highest early after axonal injury.
Insights
Axonal injury in motoneurons causes rapid down-regulation of N-methyl-D-aspartate (NMDA) receptor subunits, regardless of subsequent neuronal death. This suggests heightened excitotoxicity risk early after injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Glutamate excitotoxicity via N-methyl-D-aspartate (NMDA) receptors is implicated in motoneuron death following neonatal axotomy.
- Understanding NMDA receptor subunit expression changes is crucial for motoneuron survival after injury.
Purpose of the Study:
- To investigate the expression of NMDA receptor subunits (NR1, NR2B, NR2D mRNA and NR1 protein) in motoneurons after different types of axonal injury.
- To correlate NMDA receptor expression changes with motoneuron death following injury.
Main Methods:
- In situ hybridization to detect mRNA expression of NMDA receptor subunits.
- Immunohistochemistry to assess NR1 subunit protein levels.
- Comparison of sciatic nerve transection (neonatal and adult) and ventral root avulsion models in rats.
Main Results:
- All lesion models induced down-regulation of NR1, NR2B, and NR2D mRNA in motoneurons, detectable before significant cell death.
- Ventral root avulsion, causing the most motoneuron death, showed the strongest mRNA down-regulation.
- Reduced NR1 mRNA expression was accompanied by decreased NR1 protein levels.
Conclusions:
- Down-regulation of NMDA receptor subunits is an acute response to axonal injury in motoneurons, irrespective of neuronal death.
- Lesioned motoneurons exhibit increased susceptibility to excitotoxicity early after injury due to altered NMDA receptor expression.