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Brain Research. Developmental Brain... Jan 1997The cerebellum on the heterozygous (+/sg) staggerer mutant mouse has recently been proposed as a model system in which to study the genetic contribution to the normal... (Comparative Study)
Comparative Study
The cerebellum on the heterozygous (+/sg) staggerer mutant mouse has recently been proposed as a model system in which to study the genetic contribution to the normal process of central nervous system aging since there is significant loss of neurons from 3 to 12 months of age (Shojaeian-Zanjani, H., Mariani, J., Delhaye-Bouchaud, N., and Herrup, K. (1992) Dev. Brain Res., 67, 153-160). In the current study we extend our analysis of the changes in Purkinje cell numbers up to 24 months of age in +/sg and C57BL/6J wild-type mice. At 13 and 18 months, while wild-type Purkinje cell numbers remain unchanged, there is a 22-26% loss in the number of Purkinje cells in +/sg after which no further cell loss is observed. Between 18 and 24 months, however, a 22% loss of Purkinje cell occurs in +/+ animals, with the result that by 2 years of age, the size of the Purkinje cell population is again similar in both genotypes. Analysis of the cell loss in both the mediolateral and the anteroposterior dimensions, as well as the immunostaining of Purkinje cells in frontal sections, reveal no obvious regional variation in the Purkinje cell loss. These results suggest that in +/sg, a precocious process of aging affects the size of the Purkinje cell population.
Topics: Age Distribution; Aging; Animals; Calbindins; Cell Count; Female; Genotype; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Nerve Tissue Proteins; Purkinje Cells; S100 Calcium Binding Protein G
PubMed: 9027398
DOI: 10.1016/s0165-3806(96)00153-8 -
Biochimica Et Biophysica Acta.... Jul 2020
Topics: Animals; CRISPR-Cas Systems; Cerebellar Cortex; Dendritic Cells; Mice; Primary Cell Culture; Purkinje Cells
PubMed: 32229273
DOI: 10.1016/j.bbamcr.2020.118710 -
Developmental Neurobiology May 2007Purkinje cells are vulnerable to a number of physical, chemical, and genetic insults during development and maturity. Normal development of these cells depends on the...
Purkinje cells are vulnerable to a number of physical, chemical, and genetic insults during development and maturity. Normal development of these cells depends on the cell-cell interactions between granule and astroglial cell populations. Apoptotic death in Purkinje neurons had been shown to be associated with cell cycle activation, and new DNA synthesis is associated with Purkinje cell death in staggerer and lurcher mutant mice. Here using an in vitro organotypic slice culture model from 9 (P9) and 4 days (P4) old postnatal rats we show that the cyclin dependent kinase (cdk) inhibitors (roscovitine, olomoucine, and flavopiridol) protect the Purkinje cells from cell death. The results are more pronounced in the cerebellar sections from P4 rats. Analysis of Purkinje neurons in sections from P4 rats after 1 week of culturing showed that while there were very limited calbindin positive neurons in the untreated sections the cdk inhibitor treated sections had a notably higher number. Although treatment with cdk inhibitors inhibited Purkinje cell loss significantly, the morphology of these neurons was abnormal, with stunted dendrites and axons. Since the retinoblastoma protein (Rb) is the major pocket protein involved in determining the differentiated state of neurons we examined the effect of over-expressing Rb in the organotypic cultures. Rb overexpression significantly inhibited the Purkinje cell death and these neurons maintained their normal morphology. Thus our studies show that the cell death in Purkinje neurons observed in organotypic cultures is cell cycle dependent and the optimal survival requires Rb.
Topics: Animals; Cell Cycle; Cell Death; Cyclin-Dependent Kinases; Enzyme Inhibitors; Immunohistochemistry; Organ Culture Techniques; Purkinje Cells; Rats; Retinoblastoma Protein
PubMed: 17443827
DOI: 10.1002/dneu.20394 -
Journal of Neurobiology Feb 2000Staggerer (sg/sg) is an autosomal recessive mutation in an orphan nuclear hormone receptor gene, RORalpha, that causes a cell-autonomous, lineage-specific block in the...
Staggerer (sg/sg) is an autosomal recessive mutation in an orphan nuclear hormone receptor gene, RORalpha, that causes a cell-autonomous, lineage-specific block in the development of the Purkinje cell. Purkinje cell number is reduced by about 75-90% in adult mutants, and many of the surviving cells are small and ectopically positioned. To determine whether Purkinje cell numbers are reduced owing to either agenesis or cell death, cohorts of Purkinje cells were labeled with the birth-date marker bromodeoxyuridine (BrdU) at embryonic day (E) 10.5 or E11.5. The total number of BrdU-labeled profiles was then compared between cerebella from wild-type mice, heterozygous staggerer, and staggerer mutants at E17.5 and postnatal day (P)5. There was no significant difference between sg/sg mutants and +/sg or +/+ controls in the number of BrdU-labeled profiles or in cerebellar volumes in the E17 embryos. By P5, however, cerebellar volume was significantly reduced in the sg/sg mutants compared to controls (p <.005) and the number of BrdU-labeled profiles was reduced by 33% following E11.5 BrdU injections (p <.02). The results suggest that Purkinje cell genesis is not affected by the staggerer mutation and that Purkinje cell loss begins some time after E17. RORalpha is highly expressed in Purkinje cells by E14, so the delay between initial RORalpha expression and sg/sg Purkinje cell loss suggests that the staggerer mutation does not directly cause Purkinje cell death.
Topics: Aging; Animals; Calbindins; Cell Death; Cerebellum; Embryonic and Fetal Development; Genes, Recessive; Heterozygote; Mice; Mice, Inbred Strains; Mice, Neurologic Mutants; Nerve Tissue Proteins; Nuclear Receptor Subfamily 1, Group F, Member 1; Purkinje Cells; Receptors, Cytoplasmic and Nuclear; S100 Calcium Binding Protein G; Trans-Activators
PubMed: 10645972
DOI: 10.1002/(sici)1097-4695(20000215)42:3<323::aid-neu4>3.0.co;2-2 -
Cerebellum (London, England) Feb 2017Since the last review paper published in Cerebellum in 2002 [1], there has been a substantial increase in the number of experiments utilizing transgenic manipulations in... (Review)
Review
Since the last review paper published in Cerebellum in 2002 [1], there has been a substantial increase in the number of experiments utilizing transgenic manipulations in murine cerebellar Purkinje cells. Most of these approaches were made possible with the use of the Cre/loxP methodology and pcp2/L7 based Cre recombinase expressing transgenic mouse strains. This review aims to summarize all studies which used Purkinje cell specific transgenesis since the first use of mouse strain with Purkinje cell specific Cre expression in 2002.
Topics: Animals; Mice, Transgenic; Models, Animal; Purkinje Cells
PubMed: 26969183
DOI: 10.1007/s12311-016-0770-4 -
Movement Disorders : Official Journal... Sep 2014
Topics: Cerebellum; Essential Tremor; Female; Humans; Male; Purkinje Cells
PubMed: 25087570
DOI: 10.1002/mds.25954 -
Neuron Feb 1994To determine the role of cell-cell interactions in Purkinje cell survival and dendritic differentiation, perinatal mouse Purkinje cells were purified, and their...
To determine the role of cell-cell interactions in Purkinje cell survival and dendritic differentiation, perinatal mouse Purkinje cells were purified, and their development was analyzed in vitro. In isolation at low density, Purkinje cell survival was poor, improved by neuronal contacts, either with purified granule neurons or with Purkinje cells themselves. Moreover, coculture with specific cell populations led to widely different degrees of Purkinje cell differentiation. Purified Purkinje cells cultured alone or with an inappropriate afferent, the mossy fibers, did not progress beyond immature forms. With astroglia, Purkinje cells had thin smooth processes. Proper Purkinje cell differentiation was driven only by coculture with granule cells, resulting in dendrites with spines receiving synapses. These results suggest that Purkinje cell differentiation is regulated by local epigenetic factors, provided in large part by the granule neuron.
Topics: Afferent Pathways; Animals; Astrocytes; Cell Communication; Cell Differentiation; Cell Survival; Culture Techniques; Cytological Techniques; Granulocytes; Mice; Mice, Inbred C57BL; Nerve Fibers; Pons; Purkinje Cells
PubMed: 8110456
DOI: 10.1016/0896-6273(94)90268-2 -
Cerebellum (London, England) 2007Phocein is an intracellular protein highly expressed in neurons. It is the major partner of the striatin family members which are scaffolding proteins involved in... (Review)
Review
Phocein is an intracellular protein highly expressed in neurons. It is the major partner of the striatin family members which are scaffolding proteins involved in signaling and trafficking. Due to its association with dynamin via direct interactions with nucleotide diphosphate kinase (NDPK) and EPS15, phocein has been implicated in vesicular trafficking, acting in particular in the endocytic process. This review focuses on immuno-cytochemical studies showing the strict localization of phocein in Purkinje cell dendritic spines involved in excitatory transmission in the cerebellum of postnatal and adult rodents. Immunogold labeling sometimes detects phocein in close vicinity with endocytic-like membrane profiles suggesting that phocein plays a role in endocytosis. Furthermore, co-localization of phocein and SG2NA within spines suggests that their interactions have a functional significance in the molecular cascades that underly membrane trafficking in post-synaptic structures. As the striatin family members are highly concentrated in dendritic spines, their interactions with phocein might be involved in mediating synaptic plasticity through spine remodeling by endocytosis.
Topics: Animals; Dendritic Spines; Endocytosis; Membrane Proteins; Purkinje Cells
PubMed: 17853115
DOI: 10.1080/14734220701225912 -
Progress in Brain Research 2005Purkinje cells (PCs) present a unique cellular profile in both the cerebellum and the brain. Because they represent the only output cell of the cerebellar cortex, they... (Review)
Review
Purkinje cells (PCs) present a unique cellular profile in both the cerebellum and the brain. Because they represent the only output cell of the cerebellar cortex, they play a vital role in the normal function of the cerebellum. Interestingly, PCs are highly susceptible to a variety of pathological conditions that may involve glutamate-mediated 'excitotoxicity', a term coined to describe an excessive release of glutamate, and a subsequent over-activation of excitatory amino acid (NMDA, AMPA, and kainite) receptors. Mature PCs, however, lack functional NMDA receptors, the means by which Ca(2+) enters the cell in classic hippocampal and cortical models of excitotoxicity. In PCs, glutamate predominantly mediates its effects, first via a rapid influx of Ca(2+)through voltage-gated calcium channels, caused by the depolarization of the membrane after AMPA receptor activation (and through Ca(2+)-permeable AMPA receptors themselves), and second, via a delayed release of Ca(2+) from intracellular stores. Although physiological levels of intracellular free Ca(2+) initiate vital second messenger signaling pathways in PCs, excessive Ca(2+) influx can detrimentally alter dendritic spine morphology via interactions with the neuronal cytoskeleton, and thus can perturb normal synaptic function. PCs possess various calcium-binding proteins, such as calbindin-D28K and parvalbumin, and glutamate transporters, in order to prevent glutamate from exerting deleterious effects. Bergmann glia are gaining recognition as key players in the clearance of extracellular glutamate; these cells are also high in S-100beta, a protein with both neurodegenerative and neuroprotective abilities. In this review, we discuss PC-specific mechanisms of glutamate-mediated excitotoxic cell death, the relationship between Ca(2+) and cytoskeleton, and the implications of glutamate, and S-100beta for pathological conditions, such as traumatic brain injury.
Topics: Animals; Cell Death; Cerebellar Diseases; Glutamic Acid; Humans; Neurotoxins; Purkinje Cells
PubMed: 15661204
DOI: 10.1016/S0079-6123(04)48029-7 -
NeuroImage Aug 2023Magnetic Resonance Imaging (MRI) resolution continues to improve, making it important to understand the cellular basis for different MRI contrast mechanisms....
Magnetic Resonance Imaging (MRI) resolution continues to improve, making it important to understand the cellular basis for different MRI contrast mechanisms. Manganese-enhanced MRI (MEMRI) produces layer-specific contrast throughout the brain enabling in vivo visualization of cellular cytoarchitecture, particularly in the cerebellum. Due to the unique geometry of the cerebellum, especially near the midline, 2D MEMRI images can be acquired from a relatively thick slice by averaging through areas of uniform morphology and cytoarchitecture to produce very high-resolution visualization of sagittal planes. In such images, MEMRI hyperintensity is uniform in thickness throughout the anterior-posterior axis of sagittal sections and is centrally located in the cerebellar cortex. These signal features suggested that the Purkinje cell layer, which houses the cell bodies of the Purkinje cells and the Bergmann glia, is the source of hyperintensity. Despite this circumstantial evidence, the cellular source of MRI contrast has been difficult to define. In this study, we quantified the effects of selective ablation of Purkinje cells or Bergmann glia on cerebellar MEMRI signal to determine whether signal could be assigned to one cell type. We found that the Purkinje cells, not the Bergmann glia, are the primary of source of the enhancement in the Purkinje cell layer. This cell-ablation strategy should be useful for determining the cell specificity of other MRI contrast mechanisms.
Topics: Humans; Manganese; Cerebellum; Purkinje Cells; Neuroglia; Magnetic Resonance Imaging
PubMed: 37245561
DOI: 10.1016/j.neuroimage.2023.120198