Development of the Paramedian Lobule of the Cerebellum in Wild-Type and Tottering Mice

Isaacs, Krystyna R.; Abbott, Louise C.

doi:10.1159/000111687

Cited by 28 publications

(10 citation statements)

References 35 publications

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“…The leaner allele is recessive and causes severe generalized dystonia and ataxia (Yoon 1969; Meier and MacPike 1971; Raike, Jinnah et al 2005). The Os allele is lethal in utero when homozygous, but causes fused toes when heterozygous (Magnuson and Epstein 1984; Isaacs and Abbott 1992). Male and female breeders were paired so that each carried one Cacna1a + ; Os Os allele and one Cacna1a tg-la ; Os + allele.…”

Section: Methodsmentioning

confidence: 99%

Dystonia and cerebellar degeneration in the leaner mouse mutant

2015

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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 were 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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Section: Methodsmentioning

confidence: 99%

Dystonia and cerebellar degeneration in the leaner mouse mutant

2015

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“…Indeed, the calcium influx in tg Purkinje cells is decreased by ∼45% [15], their responses to parallel fiber stimulation are reduced by ∼50% [16], and their simple spike firing patterns show enhanced irregularities with periods of pauses and bursts [9]. Moreover, Purkinje cells in tg show morphological aberrations in that their dendritic spines make relatively frequently multiple contacts with individual parallel fiber varicosities [17] and that their somata have elongated nuclei and are reduced in size [18,19]. Interestingly, many of the morphological and physiological changes in the Purkinje cell dendrites and somata precede or coincide with the occurrence of the ataxia at the end of the first month of age suggesting that these changes form a major cause of the behavioral deficits [9,17].…”

Section: Introductionmentioning

confidence: 99%

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

et al. 2008

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Homozygous tottering mice are spontaneous ataxic mutants, which carry a mutation in the gene encoding the ion pore of the P/Q-type voltage-gated calcium channels. P/Q-type calcium channels are prominently expressed in Purkinje cell terminals, but it is unknown to what extent these inhibitory terminals in tottering mice are affected at the morphological and electrophysiological level. Here, we investigated the distribution and ultrastructure of their Purkinje cell terminals in the cerebellar nuclei as well as the activities of their target neurons. The densities of Purkinje cell terminals and their synapses were not significantly affected in the mutants. However, the Purkinje cell terminals were enlarged and had an increased number of vacuoles, whorled bodies, and mitochondria. These differences started to occur between 3 and 5 weeks of age and persisted throughout adulthood. Stimulation of Purkinje cells in adult tottering mice resulted in inhibition at normal latencies, but the activities of their postsynaptic neurons in the cerebellar nuclei were abnormal in that the frequency and irregularity of their spiking patterns were enhanced. Thus, although the number of their terminals and their synaptic contacts appear quantitatively intact, Purkinje cells in tottering mice show several signs of axonal damage that may contribute to altered postsynaptic activities in the cerebellar nuclei.

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“…Based on information gained from this investigation we will be able to carry out a more detailed investigation of the molecular mechanisms that produce the observed pattern of cerebellar granule cell death in the leaner cerebellum. (Isaacs and Abbott, 1992). Oligosyndactyly causes fusion of digits, and embryos that are homozygous for Oligosyndactyly (Os/Os) die in utero.…”

Section: Introductionmentioning

confidence: 99%

Postnatal apoptosis in cerebellar granule cells of homozygous leaner (tg la/tg la) mice

et al. 2004

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Leaner mice carry a homozygous, autosomal recessive mutation in the mouse CACNA1A gene encoding the Alpha1A subunit of P/Q-type calcium channels, which results in an out-of-frame splicing event in the carboxy terminus of the Alpha1A protein. Leaner mice exhibit severe ataxia, paroxysmal dyskinesia and absence seizures. Functional studies have revealed a marked decrease in calcium currents through leaner P/Q-type channels and altered neuronal calcium ion homeostasis in cerebellar Purkinje cells. Histopathological studies of leaner mice have revealed extensive postnatal cerebellar Purkinje and granule cell loss. We examined the temporospatial pattern of cerebellar granule cell death in the leaner mouse between postnatal days (P) 10 and 40. Our observations clearly indicate that leaner cerebellar granule cells die via an apoptotic process and that the peak time of neuronal death is P20. We did not observe a significant increase in microglial and astrocytic responses at P20, suggesting that glial responses are not a cause of neuronal cell death. We propose that the leaner cerebellar granule cell represents an in vivo animal model for low intracellular [Ca2+]-induced apoptosis. Since intracellular [Ca2+] is critical in the control of gene expression, it is quite likely that reduced intracellular [Ca2+] could activate a lethal cascade of altered gene expression leading to the apoptotic granule cell death in the leaner cerebellum.

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Development of the Paramedian Lobule of the Cerebellum in Wild-Type and Tottering Mice

Cited by 28 publications

References 35 publications

Dystonia and cerebellar degeneration in the leaner mouse mutant

Dystonia and cerebellar degeneration in the leaner mouse mutant

Purkinje Cell Input to Cerebellar Nuclei in Tottering: Ultrastructure and Physiology

Postnatal apoptosis in cerebellar granule cells of homozygous leaner (tg la/tg la) mice

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