-
Journal of Neuroscience Research May 2001Laboratory mice carrying the nonfunctional xeroderma pigmentosum group G gene (the mouse counterpart of the human XPG gene) alleles have been generated by using...
Laboratory mice carrying the nonfunctional xeroderma pigmentosum group G gene (the mouse counterpart of the human XPG gene) alleles have been generated by using gene-targeting and embryonic stem cell technology. Homozygote animals of this autosomal recessive disease exhibited signs and symptoms, such as postnatal growth retardation, reduced levels of activity, progressive ataxia and premature death, similar to the clinical manifestations of Cockayne syndrome (CS). Histological analysis of the cerebellum revealed multiple pyknotic cells in the Purkinje cell layer of the xpg homozygotes, which had atrophic cell bodies and shrunken nuclei. Further examination by an immunohistochemistry for calbindin-D 28k (CaBP) showed that a large number of immunoreactive Purkinje cells were atrophic and their dendritic trees were smaller and shorter than in wild-type littermates. These results indicated a marked degeneration of Purkinje cells in the xpg mutant cerebellum. Study by in situ detection of DNA fragmentation in the cerebellar cortex demonstrated that some deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin in situ nick labeling (TUNEL)-positive cells appeared in the granule layer of the mutant mice, but few cell deaths were confirmed in the Purkinje layer. These results suggested Purkinje cell degeneration in the mutant cerebellum was underway, in which much Purkinje cell death had not appeared, and the appearance of some abnormal cerebellar symptoms in the xpg-deficient mice was not only due to a marked Purkinje cell degeneration, but also to damage of other cells.
Topics: Animals; Animals, Newborn; Calbindins; Cerebellum; DNA-Binding Proteins; Endonucleases; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nuclear Proteins; Organ Size; Purkinje Cells; S100 Calcium Binding Protein G; Transcription Factors
PubMed: 11340641
DOI: 10.1002/jnr.1085 -
The European Journal of Neuroscience Jul 2011The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl-tRNA synthetase (Aars)...
The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl-tRNA synthetase (Aars) gene. The sticky phenotype is characterized by a small body size, a characteristic unkempt coat and neurological manifestations including marked tremor and ataxia starting at 6 weeks of age. The present study was undertaken to examine the spatiotemporal features of Purkinje cell degeneration in the sticky mouse. Purkinje cell loss was found to be both progressive and patterned, with vermal lobules VI, IX and X, crus 1 of the hemisphere, and the flocculus and paraflocculus being differentially resistant to degeneration. The pattern of Purkinje cell degeneration in sticky is not random - in general, the sphingosine kinase 1a-immunonegative Purkinje cell subset is preferentially susceptible to early cell death. In addition, zebrin II/aldolase C expression in the sticky cerebellum is profoundly downregulated, whereas the heat-shock protein 25 is both ectopically expressed in some scattered Purkinje cells and downregulated in other Purkinje cells in which it is normally expressed constitutively. Compared with many mouse mutants with patterned Purkinje cell death, in which successive stripes of cell loss are very clear, Purkinje cell loss in sticky shows a less clear-cut pattern between different Purkinje cell subtypes, with the result that preferential survival is less dramatic. This may represent a secondary consequence of the downregulation of zebrin II expression.
Topics: Animals; Ataxia; Cell Death; Cerebellum; Female; Male; Mice; Mice, Neurologic Mutants; Nerve Tissue Proteins; Purkinje Cells
PubMed: 21645134
DOI: 10.1111/j.1460-9568.2011.07725.x -
Progress in Neurobiology 1995This article reviews a series of experiments aimed at investigating the reciprocal trophic interactions which regulate the normal morphofunctional features and the... (Review)
Review
This article reviews a series of experiments aimed at investigating the reciprocal trophic interactions which regulate the normal morphofunctional features and the plasticity of the adult rodent climbing fibre-Purkinje cell system. Climbing fibre deprivation induces profound functional and structural changes in the Purkinje cell. Among others, proximal Purkinje cells dendrites become studded with numerous newly formed spines some of which are innervated by parallel fibres. These structural modifications are reversed if the Purkinje cell is reinnervated by another climbing fibre. These results indicate that the olivocerebellar input inhibits spinogenesis on proximal Purkinje cell dendrites and prevents other afferents from invading its own target domain. It is proposed that the normal distribution of synapses on the Purkinje cell dendritic tree is controlled by the interplay between climbing and parallel fibre influences on Purkinje cell dendrites. Following Purkinje cell death, the distal climbing fibre branches are withdrawn. This atrophy progresses according to the time and mode of Purkinje cell degeneration and it is reversed if the climbing fibre is provided with a new target Purkinje cell. In addition, sprouting from intact climbing fibres and collateral reinnervation of Purkinje cells can be obtained by both subtotal inferior olive lesions and transplantation of embryonic cerebellar tissue on the surface of the adult cerebellum. These results indicate that specific signals produced by non-innervated Purkinje cells are responsible for inducing and guiding climbing fibre sprouting. By contrast, contact cues would be necessary for the formation and the maintenance of terminal arbour branches and synapses. It is suggested that these interactions which control the structural plasticity following lesion or transplantation also operate during the fine structural remodelling underlying the functional plasticity in the intact cerebellar cortex.
Topics: Animals; Axons; Models, Neurological; Nerve Fibers; Nerve Regeneration; Neuronal Plasticity; Purkinje Cells
PubMed: 8966210
DOI: No ID Found -
PLoS Computational Biology Feb 2020Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These...
Recent experimental findings indicate that Purkinje cells in the cerebellum represent time intervals by mechanisms other than conventional synaptic weights. These findings add to the theoretical and experimental observations suggesting the presence of intra-cellular mechanisms for adaptation and processing. To account for these experimental results we propose a new biophysical model for time interval learning in a Purkinje cell. The numerical model focuses on a classical delay conditioning task (e.g. eyeblink conditioning) and relies on a few computational steps. In particular, the model posits the activation by the parallel fiber input of a local intra-cellular calcium store which can be modulated by intra-cellular pathways. The reciprocal interaction of the calcium signal with several proteins forming negative and positive feedback loops ensures that the timing of inhibition in the Purkinje cell anticipates the interval between parallel and climbing fiber inputs during training. We systematically test the model ability to learn time intervals at the 150-1000 ms time scale, while observing that learning can also extend to the multiple seconds scale. In agreement with experimental observations we also show that the number of pairings required to learn increases with inter-stimulus interval. Finally, we discuss how this model would allow the cerebellum to detect and generate specific spatio-temporal patterns, a classical theory for cerebellar function.
Topics: Action Potentials; Animals; Calcium; Conditioning, Classical; Humans; Purkinje Cells; Synapses
PubMed: 32040505
DOI: 10.1371/journal.pcbi.1007601 -
Nature Jun 2014Behavioural learning is mediated by cellular plasticity, such as changes in the strength of synapses at specific sites in neural circuits. The theory of cerebellar motor...
Behavioural learning is mediated by cellular plasticity, such as changes in the strength of synapses at specific sites in neural circuits. The theory of cerebellar motor learning relies on movement errors signalled by climbing-fibre inputs to cause long-term depression of synapses from parallel fibres to Purkinje cells. However, a recent review has called into question the widely held view that the climbing-fibre input is an 'all-or-none' event. In anaesthetized animals, there is wide variation in the duration of the complex spike (CS) caused in Purkinje cells by a climbing-fibre input. Furthermore, the amount of plasticity in Purkinje cells is graded according to the duration of electrically controlled bursts in climbing fibres. The duration of bursts depends on the 'state' of the inferior olive and therefore may be correlated across climbing fibres. Here we provide a potential functional context for these mechanisms during motor learning in behaving monkeys. The magnitudes of both plasticity and motor learning depend on the duration of the CS responses. Furthermore, the duration of CS responses seems to be a meaningful signal that is correlated across the Purkinje-cell population during motor learning. We suggest that during learning, longer bursts in climbing fibres lead to longer-duration CS responses in Purkinje cells, more calcium entry into Purkinje cells, larger synaptic depression, and stronger learning. The same graded impact of instructive signals for plasticity and learning might occur throughout the nervous system.
Topics: Action Potentials; Animals; Axons; Calcium; Learning; Long-Term Synaptic Depression; Macaca mulatta; Male; Motor Skills; Neuronal Plasticity; Olivary Nucleus; Purkinje Cells
PubMed: 24814344
DOI: 10.1038/nature13282 -
Biocell : Official Journal of the... Apr 2012The Purkinje cell and their synaptic contacts have been described using (1) light microsocopy, (2) transmission and scanning electron microscopy, and freeze etching... (Review)
Review
The Purkinje cell and their synaptic contacts have been described using (1) light microsocopy, (2) transmission and scanning electron microscopy, and freeze etching technique, (3) conventional and field emission scanning electron microscopy and cryofracture methods, (4) confocal laser scanning microscopy using intravital stain FM64, and (5) immunocytochemical techniques for Synapsin-I, PSD9-5, GluR1 subunit of AMPA receptors, N-cadherin, and CamKII alpha. The outer surface and inner content of plasma membrane, cell organelles, cytoskeleton, nucleus, dendritic and axonal processes have been exposed and analyzed in a three-dimensional view. The intramembrane morphology, in bi- and three-dimensional views, and immunocytochemical labeling of synaptic contacts with parallel and climbing fibers, basket and stellate cell axons have been characterized. Freeze etching technique, field emission scanning microscopy and cryofracture methods, and GluR1 immunohistochemistry showed the morphology and localization ofpostsynaptic receptors. Purkinje cell shows N-cadherin and CamKII alpha immunoreactivity. The correlative microscopy approach provides a deeper understanding of structure and function of the Purkinje cell, a new three-dimensional outer and inner vision, a more detailed study of afferent and intrinsic synaptic junctions, and of intracortical circuits.
Topics: Animals; Biomarkers; Humans; Immunoenzyme Techniques; Microscopy, Confocal; Microscopy, Electron, Scanning; Microscopy, Immunoelectron; Purkinje Cells
PubMed: 23173301
DOI: No ID Found -
Protein kinase C: its role in activity-dependent Purkinje cell dendritic development and plasticity.Cerebellum (London, England) 2003The cerebellum is a central organ in the control of motor learning and performance. In this respect, the cellular plasticity model systems of multiple climbing fiber... (Review)
Review
The cerebellum is a central organ in the control of motor learning and performance. In this respect, the cellular plasticity model systems of multiple climbing fiber elimination and long-term depression have been intensively studied. The signalling pathways involved in these plastic changes are now well understood on a molecular level and protein kinase C (PKC) activity appears to be crucially involved in both processes. Furthermore, as shown in recent studies, Purkinje cell dendritic development also critically depends on the activity of PKC. Thereby, the Ca(2+)-dependent PKC subtypes, activated by synaptic inputs through metabotropic glutamate receptors, trigger functional changes as well as long-term anatomical maturation of the Purkinje cell dendritic tree during cerebellar development at different time levels. This review summarizes these findings and forwards the hypothesis of a link between the functional mechanisms underlying LTD and the differentiation of Purkinje cell dendrites.
Topics: Animals; Cell Differentiation; Cerebellar Cortex; Dendrites; Humans; Isoenzymes; Long-Term Potentiation; Neuronal Plasticity; Protein Kinase C; Purkinje Cells
PubMed: 14509570
DOI: 10.1080/14734220310016150 -
Trends in Cognitive Sciences Jul 2017Recent electrophysiological results imply that the duration of the stimulus onset asynchrony in eyeblink conditioning is encoded by a mechanism intrinsic to the... (Review)
Review
Recent electrophysiological results imply that the duration of the stimulus onset asynchrony in eyeblink conditioning is encoded by a mechanism intrinsic to the cerebellar Purkinje cell. This raises the general question - how is quantitative information (durations, distances, rates, probabilities, amounts, etc.) transmitted by spike trains and encoded into engrams? The usual assumption is that information is transmitted by firing rates. However, rate codes are energetically inefficient and computationally awkward. A combinatorial code is more plausible. If the engram consists of altered synaptic conductances (the usual assumption), then we must ask how numbers may be written to synapses. It is much easier to formulate a coding hypothesis if the engram is realized by a cell-intrinsic molecular mechanism.
Topics: Action Potentials; Electrophysiological Phenomena; Purkinje Cells; Synapses
PubMed: 28522379
DOI: 10.1016/j.tics.2017.04.012 -
Cerebellum (London, England) Dec 2016Postmortem studies have reported Purkinje cell loss in essential tremor (ET), and we recently demonstrated a significant increase in the mean distance between Purkinje...
Postmortem studies have reported Purkinje cell loss in essential tremor (ET), and we recently demonstrated a significant increase in the mean distance between Purkinje cell bodies (i.e., a larger gap length distance) in ET cases vs. controls, likely reflecting a disease-associated reduction in Purkinje cells. We now analyze the regularity of distribution of Purkinje cells along the Purkinje cell layer to determine whether there is greater disorganization in ET cases than in age-matched controls. A standard parasagittal, formalin-fixed, tissue block was harvested from the neocerebellum of 50 ET cases and 25 age-matched controls. The gap length distance (μm) between Purkinje cells was quantified using a nearest neighbor analysis in which the distance between each Purkinje cell body was measured in OpenLAB software, version 5 (Improvision, Waltham, MA) by drawing a freehand line between adjacent Purkinje cell bodies along the entirety of the Purkinje cell layer within a given image. We analyzed the subject-specific variation in the organization of Purkinje cells along the Purkinje cell layer. The 50 ET cases and 25 controls were similar in age at death, gender, and brain weight. Overall, greater variation in gap length distance (i.e., more disorganization) was associated with greater gap length distance (p < 0.001) and younger age (p = 0.020). However, the variation in the Purkinje cell gap length distance (i.e., Purkinje cell organization) did not differ in ET cases and controls (p = 0.330). We observed that the regularity of the distribution of Purkinje cells along the Purkinje cell layer did not differ between ET cases and controls. Several alternative biological interpretations for this finding are discussed.
Topics: Aged, 80 and over; Cell Count; Essential Tremor; Female; Fixatives; Formaldehyde; Humans; Image Processing, Computer-Assisted; Male; Microscopy; Purkinje Cells; Software; Tissue Fixation
PubMed: 26563297
DOI: 10.1007/s12311-015-0742-0 -
Learning & Memory (Cold Spring Harbor,... 2006The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of... (Comparative Study)
Comparative Study
The current study examined the effects of globally depleting Purkinje cells in the cerebellar cortex with the immunotoxin OX7-saporin on acquisition and extinction of delay eyeblink conditioning in rats. Rats were given OX7-saporin or saline 2 wk before the start of eyeblink conditioning. The rats that reached a performance criterion of two consecutive days with 80% or greater conditioned responses were given 5 d of extinction training followed by 2 d of reacquisition training. Rats that received infusions of OX7-saporin had 77.2%-97.9% Purkinje cell loss and exhibited impaired acquisition and extinction. The amount of Purkinje cell loss was correlated with the magnitude of the acquisition and extinction impairments. The highest correlations between Purkinje cell number and the rate of acquisition were in lobule HVI and the anterior lobe. The highest negative correlation between Purkinje cell number and the percentage of conditioned responses during extinction was in the anterior lobe. The results indicate that cerebellar Purkinje cells, particularly in the anterior lobe and lobule HVI, play significant roles in acquisition and extinction of eyeblink conditioning.
Topics: Analysis of Variance; Animals; Antibodies, Monoclonal; Association Learning; Cell Count; Cerebellum; Conditioning, Eyelid; Extinction, Psychological; Immunoconjugates; Immunotoxins; Male; N-Glycosyl Hydrolases; Neurotoxins; Purkinje Cells; Rats; Rats, Long-Evans; Regression Analysis; Ribosome Inactivating Proteins, Type 1; Saporins
PubMed: 16741286
DOI: 10.1101/lm.168506