Abstract
BackgroundThe localisation of AMPA and NMDA receptor subunits was studied in a model of degeneration of cervical spinal motoneurons, the wobbler mouse. Cervical regions from early or late symptomatic wobbler mice (4 or 12 weeks of age) were compared to lumbar tracts (unaffected) and to those of healthy mice.ResultsNo differences were found in the distribution of AMPA and NMDA receptor subunits at both ages. Western blots analysis showed a trend of reduction in AMPA and NMDA receptor subunits, mainly GluR1 and NR2A, exclusively in the cervical region of late symptomatic mice in the triton-insoluble post-synaptic fraction but not whole homogenates. Colocalisation experiments evidenced the expression of GluR1 and NR2A receptors in activated astrocytes from the cervical spinal cord of wobbler mice, GluR2 did not colocalise with GFAP positive cells. No differences were found in the expression of AMPA and NMDA receptor subunits in the lumbar tract of wobbler mice, where neither motoneuron loss nor reactive gliosis occurs.ConclusionIn late symptomatic wobbler mice altered levels of GluR1 and NR2A receptor subunits may be a consequence of motoneuron loss rather than an early feature of motoneuron vulnerability.
Highlights
The localisation of amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate ionotropic (AMPA) and NMDA receptor subunits was studied in a model of degeneration of cervical spinal motoneurons, the wobbler mouse
Motoneurons from the cervical region of wobbler mice showed weaker staining and a diffuse immunoreactivity not selective to neurons, colocalisation experiments have demonstrated to be related to glial cells; this novel pattern of GluR1 staining was evident in motoneurons of 12-week-old wobbler mice (Q)
The lack of lowering of AMPA and NMDA receptor subunits levels in Triton-Insoluble post-synaptic Fraction (TIF) from early symtpomatic wobbler mice, when at least 25% of motoneurons are lost, might be to due to the fact that post-synaptic densities are related to motoneurons, and our immunohistochemical experiments clearly showed that AMPA and NMDA receptor subunits are expressed in almost all neuronal populations, the dorsal horn neurons
Summary
The localisation of AMPA and NMDA receptor subunits was studied in a model of degeneration of cervical spinal motoneurons, the wobbler mouse. Evidence of abnormal glutamate metabolism and impaired expression of the glial glutamate transporter 2 (EAAT2) in ALS patients suggests that glutamate-induced excitotoxicity plays a key role in generating this disease [5]. Glutamate overstimulation can act through both the N-methyl-D-aspartate (NMDA) receptors and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate ionotropic (AMPA) receptors, generating an excessive influx of Ca++ and Na+ in neurons and the subsequent activation of damaging pathways, leading to motoneuron death [5]. Another source of motoneuron vulnerability involves a change of Ca++ conductance in AMPA receptors. In a subset of ALS patients, the editing of GluR2 is defective, causing increased Ca++ permeability to the AMPA receptor [8], that enhances Ca++-dependent pathways and leads to motoneurons death [9]
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