The numerical matching of source and target populations in the CNS: the inferior olive to Purkinje cell projection

Herrup, Karl; Zanjani, Hadi Shojaeian; Panzini, Lisa; Sunter, Karen; Mariani, Jean

doi:10.1016/0165-3806(96)00069-7

Cited by 44 publications

(24 citation statements)

References 40 publications

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“…These raw values were overestimates, as cell nuclei can be split during sectioning and may thus appear in more than one section; therefore, the corrected number of Purkinje cells was obtained by multiplying the raw values by the Hendry correction factor for each animal (Hendry, 1976). We chose to use this traditional correction factor for our cell counts instead of more recently developed stereological techniques (Williams & Rakic, 1988;Andersen et al, 1992), so that our results would be directly comparable with previously published Purkinje cell counts, including our own (Herrup & Mullen, 1979;Zanjani et al, 1992;Herrup et al, 1996;Doulazmi et al, 1999).…”

Section: Histologymentioning

confidence: 89%

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

Doulazmi¹,

Hadj-Sahraoui²,

Frédéric³

et al. 2002

Journal of Neurogenetics

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Mice homozygous for the recessive, cerebellar affected mutations nervous and Purkinje cell degeneration display an almost complete loss of Purkinje cells during their first two postnatal months. We have recently shown a progressive and age-related loss of Purkinje cells in mutant mice heterozygous for mutations apparently recessive, such as staggerer and reeler, and have thus chosen to investigate whether a similar Purkinje cell loss occurred with aging in +/nr and +/pcd heterozygous mice. Purkinje cells were counted on serial sections stained with thionin obtained from 17-month-old male and female heterozygous mice and their respective wild-type controls. In the case of the +/nr and wild-type mice, no difference in cell counts was observed. However, +/pcd mice had significantly fewer (-18%) Purkinje cells (143.700+/-5.400) than control wild-types (175.100+/-2.300); p<0.0001) at 17 months. These results extend our previous findings and further support the idea that apparently recessive neurological mutations may exert, at the heterozygous state, a deleterious effect upon Purkinje cells during the aging process.

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Section: Histologymentioning

confidence: 89%

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

Doulazmi¹,

Hadj-Sahraoui²,

Frédéric³

et al. 2002

Journal of Neurogenetics

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“…The number of granule cells per hemi-cerebellum was significantly higher in Grid2 Lc/ϩ ;BaxϪ/Ϫ cerebella (10.80 Ϯ 0.78 ϫ 10 6 ) compared with Grid2 Lc/ϩ ;Baxϩ/ϩ (3.16 Ϯ 0.35 ϫ 10 6 ) and Grid2 Lc/ϩ ;Baxϩ/Ϫ (2.87 Ϯ 0.13 Ϫ 10 6 ) cerebella (see Fig. 4B Sixty to 75% of the inferior olivary neurons normally degenerate in Grid2 Lc/ϩ mice following the death of their Purkinje cell targets (Caddy et al, 1979;Heckroth et al, 1991;Herrup et al, 1996). Fifty-four percent of these neurons have disappeared by P26 (Caddy and Biscoe, 1979).…”

Section: Bax Deletion Inhibits Granule Cell Death In Lurcher Micementioning

confidence: 99%

“…In the olivocerebellar system, surgical and genetic lesions have shown that the survival of olivary neurons and granule cells is dependent on interactions with their PC targets (Harkmark, 1956;Sotelo and Changeux, 1974;Caddy and Biscoe, 1979;Wetts and Herrup, 1982a,b;Zanjani et al, 1990;Vogel et al, 1991;Herrup et al, 1996). Many olivary neurons and granule cells undergo apoptotic cell death when deprived of their target Smeyne et al, 1995).…”

Section: Granule Cell Survival and Olivary Neuron Deathmentioning

confidence: 99%

BaxInactivation in Lurcher Mutants Rescues Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary Neurons

2000

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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 (Grid2 Lc/ϩ ) 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 Grid2 Lc/ϩ neurodegeneration, double mutants with Grid2 Lc/ϩ mice and Bax knock-out mice (BaxϪ/Ϫ) 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 Grid2 Lc/ϩ ;BaxϪ/Ϫ animals. From postnatal day 15 (P15) to P60, the number of granule cells in Grid2 Lc/ϩ ;BaxϪ/Ϫmice did not significantly change and was significantly increased compared with the number found in Grid2 Lc/ϩ ;Baxϩ/ϩ mice. Granule cell number in P60 Grid2 Lc/ϩ ;BaxϪ/Ϫ mice corresponded to 70% of the number found in wild-type mice. Our results show that Bax inactivation in Grid2 Lc/ϩ 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.

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“…The early cerebellar atrophy is related to a massive reduction in the number of PCs (reduced by about 80% Doulazmi et al, 2001) and study of chimeras has shown that this defect is due to an intrinsic action of the gene in the PCs (Herrup & Mullen, 1979b). The lack of Purkinje cells induces a near total loss of their afferents, the granule cells and inferior olivary neurons, during the first postnatal month (Herrup et al, 1996). Part of the granule cell loss is due to the action of RORa on one of its target gene in the cerebellum, sonic hedgehog, since its addition to Rora sg=sg organotypic cultures restores granule precursor proliferation (Gold et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

“…The most obvious phenotype of homozygous Rora knockout mice (Rora À=À ) and natural RORa deficient staggerer (Rora sg=sg ) mice is an ataxic gait, associated with a massive cerebellar degeneration due to a defect in Purkinje cell development (Herrup et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

CEREBELLAR PURKINJE CELL LOSS IN HETEROZYGOUSRORA^+/−MICE: A LONGITUDINAL STUDY

Doulazmi

Capone

Frédéric

et al. 2006

Journal of Neurogenetics

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The staggerer (sg) mutation is a spontaneous deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of RORalpha activity. The homozygous Rorasg/sg mutant mouse, whose most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes. The heterozygous Rora+/sg is able to develop a cerebellum that is qualitatively normal but which suffers a significant loss of cerebellar neuronal cells with advancing age. A truncated protein synthesized by the mutated allele may play a role both in Rorasg/sg and Rora+/sg. To determine the effects during life span of true haplo-insufficiency of the RORalpha protein, derived from the invalidation of the gene, we compared the evolution of Purkinje cell numbers in heterozygous Rora knock-out males (Rora+/-) and in their wild-type counterparts from 1 to 24 months of age. We also compared the evolution of Purkinje cell (PC) numbers in Rora+/- and Rora+/sg males from 1 to 9 months. The main finding is that in Rora+/- mice, for which only one-half the normal amount of protein is produced, the deficit was established as early as 1 month and did not change during the animals' adult lifespans. Thus, the effects of aging on PC number were apparent much earlier in Rora+/- than in Rora+/sg, although at 24 months of age the degrees of deficit were similar.

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The numerical matching of source and target populations in the CNS: the inferior olive to Purkinje cell projection

Cited by 44 publications

References 40 publications

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

BaxInactivation in Lurcher Mutants Rescues Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary Neurons

CEREBELLAR PURKINJE CELL LOSS IN HETEROZYGOUSRORA^+/−MICE: A LONGITUDINAL STUDY

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The numerical matching of source and target populations in the CNS: the inferior olive to Purkinje cell projection

Cited by 44 publications

References 40 publications

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

Diminishing Purkinje Cell Populations in the Cerebella of Aging Heterozygous Purkinje Cell Degeneration but Not Heterozygous Nervous Mice

BaxInactivation in Lurcher Mutants Rescues Cerebellar Granule Cells But Not Purkinje Cells or Inferior Olivary Neurons

CEREBELLAR PURKINJE CELL LOSS IN HETEROZYGOUSRORA+/−MICE: A LONGITUDINAL STUDY

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CEREBELLAR PURKINJE CELL LOSS IN HETEROZYGOUSRORA^+/−MICE: A LONGITUDINAL STUDY