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The Journal of Neuroscience, July 15, 2000, 20(14):5339-5345
Bax Inactivation in Lurcher Mutants Rescues
Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary
Neurons
Fekrije
Selimi1,
Michael W.
Vogel2, and
Jean
Mariani1
1 Laboratoire Développement et Vieillissement du
Système Nerveux, Institut des Neurosciences, Centre National de
la Recherche Scientifique, Unité Mixte de Recherche 7624, Université Pierre et Marie Curie, 75005 Paris, France, and
2 Maryland Psychiatric Research Center, University of
Maryland Medical School, Baltimore, Maryland 21228
Lurcher is a gain-of-function mutation in the  2 glutamate
receptor gene (Grid2) that turns the receptor into a
leaky ion channel. The expression of the Lurcher gene in heterozygous
(Grid2Lc/+) mutants induces the death of
almost all Purkinje cells starting from the second postnatal week.
Ninety percent of the granule cells and 60-75% of the inferior
olivary neurons die because of the loss of their target neurons, the
Purkinje cells. The apoptotic nature of the neurodegeneration has been
demonstrated previously by the presence of activated caspase-3 and DNA
fragmentation. Bax, a pro-apoptotic gene of the Bcl-2
family, has been shown to be involved in developmental neuronal death.
To study the role of Bax in
Grid2Lc/+ neurodegeneration, double mutants
with Grid2Lc/+ mice and Bax
knock-out mice (Bax /) were generated.
Bax deletion had no effect on the death of Purkinje
cells and inferior olivary neurons, although a temporary rescue of some
Purkinje cells could be detected in P15
Grid2Lc/+;Bax/ animals. From postnatal
day 15 (P15) to P60, the number of granule cells in
Grid2Lc/+;Bax/mice did not significantly
change and was significantly increased compared with the number found
in Grid2Lc/+;Bax+/+ mice. Granule cell
number in P60 Grid2Lc/+;Bax/ mice
corresponded to 70% of the number found in wild-type mice. Our results
show that Bax inactivation in
Grid2Lc/+ mice does not rescue intrinsic
Purkinje cell death or the target-related cell death of olivary
neurons, but Bax inactivation does inhibit persistently
target-related cell death in cerebellar granule cells.
Key words:
Lurcher; Bax; Purkinje cell; granule cell; inferior olive; neuronal death
Copyright © 2000 Society for Neuroscience 0270-6474/00/20145339-07$05.00/0
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