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Survival of interneurons and parallel fiber synapses in a cerebellar cortex deprived of Purkinje cells: Studies in the double mutant mouse Grid2 Lc /+ ; Bax −/−
Author(s) -
Zanjani S. Hadi,
Selimi Fekrije,
Vogel Michael W.,
Haeberlé AnneMarie,
Boeuf Julien,
Mariani Jean,
Bailly Yannick J.
Publication year - 2006
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.21017
Subject(s) - cerebellum , cerebellar cortex , purkinje cell , biology , parallel fiber , granule cell , granular layer , neuroscience , deep cerebellar nuclei , microbiology and biotechnology , mutant , axon , programmed cell death , apoptosis , central nervous system , gene , biochemistry , dentate gyrus
Abstract The Lurcher mutation in the Grid2 gene causes the cell autonomous death of virtually all cerebellar Purkinje cells and the target‐related death of 90% of the granule cells and 60–75% of the olivary neurons. Inactivation of Bax , a pro‐apoptotic gene of the Bcl‐2 family, in heterozygous Lurcher mutants ( Grid2 Lc /+ ) rescues ∼60% of the granule cells, but does not rescue Purkinje or olivary neurons. Given the larger size of the cerebellar molecular layer in Grid2 Lc /+ ; Bax −/− double mutants compared to Grid2 Lc /+ mutants, we analyzed the survival of the stellate and basket interneurons as well as the synaptic connectivity of parallel fibers originating from the surviving granule cells in the absence of their Purkinje cell targets in the Grid2 Lc /+ ; Bax −/− cerebellum. Quantification showed a significantly higher density of interneurons (∼60%) in the molecular layer of the Grid2 Lc /+ ; Bax −/− mice compared to Grid2 Lc /+ , suggesting that interneurons are subject to a BAX‐dependent target‐related death in the Lurcher mutants. Furthermore, electron microscopy showed the normal ultrastructural aspect of a number of parallel fibers in the molecular layer of the Grid2 Lc /+ ; Bax −/− double mutant mice and preserved their numerous synaptic contacts on interneurons, suggesting that interneurons could play a trophic role for axon terminals of surviving granule cells. Finally, parallel fibers varicosities in the double mutant established “pseudo‐synapses” on glia as well as displayed autophagic profiles, suggesting that the connections established by the parallel fibers in the absence of their Purkinje cell targets were subject to a high turnover involving autophagy. J. Comp. Neurol. 497:622–635, 2006. © 2006 Wiley‐Liss, Inc.