Correspondence

Amyotrophic Lateral Sclerosis

N Engl J Med 2001; 345:1131-1132October 11, 2001

Article

To the Editor:

In their review of amyotrophic lateral sclerosis (ALS) Rowland and Shneider (May 31 issue)1 state that “the selective vulnerability of motor neurons” to glutamate may be explained by “the fact that the expression of GluR2 in motor neurons is normally lower than in other neurons.” However, there is currently no convincing evidence that the expression of GluR2 is lower in motor neurons than in less vulnerable neurons. More than 10 groups have reported on qualitative studies of the distribution of GluR2 in the spinal cord. With the exception of the group cited by the authors, all the groups found clear evidence of GluR2 expression in motor neurons in normal spinal cord sections from humans and rodents.2 Electron-microscopical studies in mice revealed no significant difference in the percentage of GluR2-labeled synapses or the amount of GluR2 labeling per synapse between vulnerable ventral-horn regions and the dorsal horn.3 Also, quantitative electrophysiological measurements reflecting the relative abundance of edited GluR2 incorporated into functional receptors did not differ significantly between motor neurons and dorsal-horn neurons in rats.4 Finally, vulnerable hypoglossal motor neurons and resistant oculomotor neurons appear to express similar levels of GluR2.5

As the authors point out, it is possible that changes in the expression of glutamate receptors occur in patients with ALS. However, the available data argue against, rather than support, the notion that lack of GluR2 explains the selective vulnerability of normal motor neurons to glutamate.

Wim Vandenberghe, M.D., Ph.D.
University Hospital Gasthuisberg, 3000 Leuven, Belgium
wim.vandenberghe@uz.kuleuven.ac.be

James R. Brorson, M.D.
University of Chicago, Chicago, IL 60637

5 References

1. 1

   Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001;344:1688-1700
   Full Text | Web of Science | Medline

2. 2

   Tomiyama M, Rodriguez-Puertas R, Cortes R, et al. Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization. Neuroscience 1996;75:901-915
   CrossRef | Web of Science | Medline

3. 3

   Morrison BM, Janssen WGM, Gordon JW, Morrison JH. Light and electron microscopic distribution of the AMPA receptor subunit, GluR2, in the spinal cord of control and G86R mutant superoxide dismutase transgenic mice. J Comp Neurol 1998;395:523-534
   CrossRef | Web of Science | Medline

4. 4

   Vandenberghe W, Robberecht W, Brorson JR. AMPA receptor calcium permeability, GluR2 expression, and selective motoneuron vulnerability. J Neurosci 2000;20:123-132
   Web of Science | Medline

5. 5

   Laslo P, Lipski J, Nicholson LFB, Miles GB, Funk GD. GluR2 AMPA receptor subunit expression in motoneurons at low and high risk for degeneration in amyotrophic lateral sclerosis. Exp Neurol 2001;169:461-471
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Our statement that lower GluR2 levels in motor neurons may account in part for the selective vulnerability of motor neurons to glutamate was based not only on the one study we cited1 but also on others, including the study by Tomiyama et al. that Drs. Vandenberghe and Brorson cite.2 Tomiyama et al. stated that the abundance of GluR2 varies in spinal neurons and that dorsal-horn neurons “may have lower Ca²⁺ permeability and be more resistant to excitotoxicity induced by AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-receptor agonists than neurons in other regions” (e.g., ventral motor neurons). In another study, GluR2 was not found in identified motor neurons from dissociated spinal cord cultures.3 In contrast, Drs. Vandenberghe and Brorson and their colleagues and other groups found no significant differences in GluR2 levels in cells according to whether they were more or less vulnerable to AMPA toxicity. Perhaps the explanation for this discrepancy is technical.

In any case, differences in levels of GluR2 messenger RNA (mRNA) or protein may be only one way to explain the selective vulnerability of motor neurons. Whole-cell analysis of GluR2 expression by molecular, immunocytochemical, or electrophysiological means cannot rule out subcellular differences in the subunit composition and channel permeability of AMPA receptors. The selective vulnerability of motor neurons to glutamate — mediated by calcium-permeable AMPA–kainate receptors — could be modified by any of several cellular conditions: differences in levels of GluR2, variable editing of GluR2 mRNA, post-translational modifications of GluR2, variations in the subunit composition of AMPA–kainate receptors, or synaptic localization of edited GluR2 that lacks AMPA-receptor activity.

The contributions of Drs. Vandenberghe and Brorson are important. Future studies should clarify the role of GluR2 in calcium-mediated excitotoxicity and the pathogenesis of ALS.

Lewis P. Rowland, M.D.
Neil A. Shneider, M.D., Ph.D.
Columbia–Presbyterian Medical Center, New York, NY 10032
lpr1@columbia.edu

3 References

1. 1

   Williams TL, Day NC, Ince PG, Kamboj RK, Shaw PJ. Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors: a molecular determinant of selective vulnerability in amyotrophic lateral sclerosis. Ann Neurol 1997;42:200-207
   CrossRef | Web of Science | Medline

2. 2

   Tomiyama M, Rodriguez-Puertas R, Cortes R, et al. Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization. Neuroscience 1996;75:901-915
   CrossRef | Web of Science | Medline

3. 3

   Bar-Peled O, O'Brien RJ, Morrison JH, Rothstein JD. Cultured motor neurons possess calcium-permeable AMPA/kainate receptors. Neuroreport 1999;10:855-859
   CrossRef | Web of Science | Medline