The Journal of Neuroscience, October 15, 1998, 18(20):8278-8291
Axonal Injury Alters Alternative Splicing of the Retinal NR1
Receptor: the Preferential Expression of the NR1b Isoforms Is
Crucial for Retinal Ganglion Cell Survival
Michael R.
Kreutz1, 2,
Tobias M.
Böckers2, 3,
Jürgen
Bockmann2, 3,
Constanze I.
Seidenbecher1,
Bettina
Kracht1, 2,
Christian K.
Vorwerk1,
Jens
Weise1, and
Bernhard A.
Sabel1
1 AG Molecular and Cellular Neurobiology,
Institute of Medical Psychology, Otto-von-Guericke University, 39120 Magdeburg, Germany, 2 Department of Neurochemistry and
Molecular Biology, Leibniz-Institute for Neurobiology, 39118 Magdeburg,
Germany, and 3 AG Molecular Neuroendocrinology, Institute
of Anatomy, Westfälische-Wilhelms University, 48129 Münster, Germany
Cellular-specific splicing of the retinal NMDAR1 receptor (NR1) and
expression of NMDAR2 receptor (NR2) subunits in response to optic nerve
injury was investigated by in situ hybridization in
adult rats. A controlled optic nerve crush led to a clear alteration in
the expression of alternatively spliced NR1 variants in the retinal
ganglion cell layer (GCL). The NR1-2b and NR1-4b isoforms were
preferentially expressed between 2 d and 1 week after injury, whereas expression for all other isoforms remained either unchanged or
decreased to barely detectable levels within 4 weeks. Cellular silver
grain density for NR2 subunits also declined in the GCL after trauma.
To directly test the hypothesis that NR1b expression is crucial
for cell survival after axonal trauma, we administered intraocularly an
antisense oligonucleotide against the NR1b isoform 2 and 3 d after
injury. This led to a drastic loss of retrogradely labeled retinal
ganglion cells (RGCs). Antisense targeting clearly reduced retinal NR1
protein levels, as judged by Western blot analysis, but had no effect
on the cell number in control retinas. These findings point
toward injury-specific changes in alternative splicing of the NR1
receptor, which are crucial for the survival of RGCs after partial
axonal trauma. We therefore propose that this reflects an adaptive,
rather than a pathogenic, cellular response to neurotrauma.
Key words:
NMDA receptors; NR1; NR2; alternative splicing; retina; antisense targeting; optic nerve crush; in situ
hybridization; RT-PCR; Western blots; lesion
Copyright © 1998 Society for Neuroscience 0270-6474/98/18208278-14$05.00/0
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