Cerebellar cell degeneration in the leaner mutant mouse

doi:10.1016/0306-4522(82)90129-4

Neuroscience

Volume 7, Issue 9, September 1982, Pages 2185-2196

https://doi.org/10.1016/0306-4522(82)90129-4 Get rights and content

Abstract

Leaner is an autosomal recessive mutation of the mouse which results in a severe ataxia accompanied by cellular losses in the cerebellar cortex. The purpose of this report is to construct a developmental profile of these losses. Of the three cerebellar cell types studied, the granule cells are the first to show obvious degenerative changes. Pycnotic cells are numerous in the internal granule cell layer at postnatal day 10, and, while they are found throughout the cortex, they are more concentrated in the anterior folia. Initially, there is a strong tendency for the pycnotic cells to be located in the deep half of the internal granule cell layer. By four postnatal months the rate of loss has slowed but the finding of occasional pycnotic cells in animals up to one year old suggests it continues for the life of the animal. Quantitative analysis of Purkinje and Golgi cells in leaner cerebella reveals a progressive loss of these cells as well. The number of Golgi cells falls uniformly to around half of the wild-type number. By contrast, the Purkinje cells show much more extensive degeneration. Further, the rate of cell death shows a regional variation; it is significantly more rapid in anterior folia. Overall, the number of Purkinje cells in leaner falls to about one-fifth of the wild-type number. The loss of both Purkinje and Golgi cells occurs late relative to the major events of cerebellar maturation. Significant cell loss is not observed until the end of the first postnatal month. For the next 4 to 6 weeks there is extensive cell death but, rather than abating, it appears to continue at a low rate for the life of the animal.

It is hoped that this developmental sketch of the leaner defect will stimulate others to approach leaner and its alleles, tottering and rolling, as models for heterogeneity of disease expression.

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Citation Excerpt :
Different Cacan1a mutations in rodent models cause a similarly broad array of disorders, including generalized dystonia or ataxia, paroxysmal dystonia, epilepsy and migraine (Meier and MacPike, 1971; Doyle et al., 1997; van den Maagdenberg et al., 2004; Raike et al., 2005; Tokuda et al., 2007; Shirley et al., 2008). We selected the leaner mutant not because of its relationship to a variety of different disorders, but because it is known to have severe chronic dystonia (Yoon, 1969; Meier and MacPike, 1971; Doyle et al., 1997) that is associated with abnormal physiological activity and slow degeneration of cerebellar Purkinje neurons (Meier and MacPike, 1971; Herrup and Wilczynski, 1982; Heckroth and Abbott, 1994; Lau et al., 2004; Walter et al., 2006; Ovsepian and Friel, 2008, 2012). Thus it provides an ideal tool to address questions regarding the relationships between dystonia and cerebellar dysfunction.
Cerebellar degeneration is traditionally associated with ataxia. Yet, there are examples of both ataxia and dystonia occurring in individuals with cerebellar degeneration. There is also substantial evidence suggesting that cerebellar dysfunction alone may cause dystonia. The types of cerebellar defects that may cause ataxia, dystonia, or both have not been delineated. In the current study, we explored the relationship between cerebellar degeneration and dystonia using the leaner mouse mutant. Leaner mice have severe dystonia that is associated with dysfunctional and degenerating cerebellar Purkinje cells. Whereas the density of Purkinje cells was not significantly reduced in 4 week-old leaner mice, approximately 50% of the neurons was lost by 34 weeks of age. On the other hand, the dystonia and associated functional disability became significantly less severe during this same interval. In other words, dystonia improved as Purkinje cells were lost, suggesting that dysfunctional Purkinje cells, rather than Purkinje cell loss, contribute to the dystonia. These results provide evidence that distorted cerebellar function may cause dystonia and support the concept that different types of cerebellar defects can have different functional consequences.
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Several mouse models exist that carry mutations in the orthologous mouse Cacna1a gene. Most of these mutants, including Tottering (tg), Rolling Nagoya (tgrol) and Leaner (tgla), arose spontaneously and display complex phenotypes of cerebellar ataxia, often paired with absence epilepsy and/or other motor phenotypes such as dyskinesia and dystonia (Green and Sidman, 1962; Oda, 1973; Herrup and Wilczynski, 1982). In addition, transgenic knock-in (KI) mouse models were generated which harbor the human FHM1 missense mutations R192Q (R192Q KI) and S218L (S218L KI) in the Cacna1a gene (van den Maagdenberg et al., 2004, 2010).
Ataxia is the predominant clinical manifestation of cerebellar dysfunction. Mutations in the human CACNA1A gene, encoding the pore-forming α₁ subunit of Ca_V2.1 (P/Q-type) calcium channels, underlie several neurological disorders, including Episodic Ataxia type 2 and Familial Hemiplegic Migraine type 1 (FHM1).
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Cerebellar cell degeneration in the leaner mutant mouse

Abstract

Brain Res.

Expl Neurol.

Brain Res.

Brain Res.

Changes in the cerebellar noradrenaline nerve terminals of the neurological murine mutant rolling mouse Nagoya: a histofluorescence analysis

Anat. Human Biol. Neurobiol. Neurophysiol.

Tottering, a neuromuscular mutation in the mouse and its linkage with oligosyndactylism

J. Hered.

A method to correct adequately for the change in neuronal size when estimating numbers after nerve growth factor treatment

J. Neurocytol.

A formaldehyde-glutaraldehyde fixative of high osmolarity for use in electron-microscopy

J. Cell Biol.

Methods for the counting of neurons

On the ontogenetic development of the cerebellum (nuclei, fissures, and cortex) of the rat with special reference to regional variations in corticogenesis

J. Hirnforsch.

Cerebellar organization in the light of cerebellar nuclear morphology and cerebellar corticogenesis

Ultrastructural changes in the mitochondria of cerebellar Purkinje cells of nervous mutant mice

J. Cell Biol.

Mutant mouse tottering. Selective increase of locuscoeruleus axons in a defined single locus mutation