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Jean-paul G. Vonsattel - One of the best experts on this subject based on the ideXlab platform.
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Purkinje Cell loss in essential tremor random sampling quantification and nearest neighbor analysis
Movement Disorders, 2016Co-Authors: Matthew Choe, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Introduction Purkinje Cell loss has been documented in some, although not all, postmortem studies of essential tremor. Hence, there is considerable controversy concerning the presence of Purkinje Cell loss in this disease. To date, few studies have been performed. Methods Over the past 8 years, we have assembled 50 prospectively studied cases and 25 age-matched controls; none were reported in our previous large series of 33 essential tremor and 21 controls. In addition to methods used in previous studies, the current study used a random sampling approach to quantify Purkinje Cells along the Purkinje Cell layer with a mean of 217 sites examined in each specimen, allowing for extensive sampling of the Purkinje Cell layer within the section. For the first time, we also quantified the distance between Purkinje Cell bodies—a nearest neighbor analysis. Results In the Purkinje Cell count data collected from fifteen 100 × fields, cases had lower counts than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli; all P < 0.001). Purkinje Cell linear density was also lower in cases than controls (all P < 0.001). Purkinje Cell linear density obtained by random sampling was similarly lower in cases than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli, all P ≤ 0.005). In agreement with the quantitative Purkinje Cell counts, the mean distance from one Purkinje Cell body to another Purkinje Cell body along the Purkinje Cell layer was greater in cases than controls (P = 0.002). Conclusions These data provide support for the neurodegeneration of cerebellar Purkinje Cells in essential tremor. © 2016 International Parkinson and Movement Disorder Society
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reduced Purkinje Cell dendritic arborization and loss of dendritic spines in essential tremor
Brain, 2014Co-Authors: Elan D Louis, Etty Cortes, Jean-paul G. Vonsattel, Rachel Babij, Michelle Lee, Phyllis L FaustAbstract:Based on accumulating post-mortem evidence of abnormalities in Purkinje Cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje Cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje Cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P = 0.01), 465.9 versus 592.5 µm (branch length, P = 0.01), 22.5 versus 29.0 (maximum branch order, P = 0.001), and 165.3 versus 311.7 (number of terminations, P = 0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians = 0.82 versus 1.02 µm−1, P = 0.03). Our demonstration of regressive changes in Purkinje Cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje Cell biology in this disease, which affects multiple neuronal Cellular compartments including their axon, Cell body, dendrites and spines.
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abnormal climbing fibre Purkinje Cell synaptic connections in the essential tremor cerebellum
Brain, 2014Co-Authors: Elan D Louis, Jean-paul G. Vonsattel, Phyllis L Faust, Arnulf H KoeppenAbstract:Structural changes in Purkinje Cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje Cells, and climbing fibre-Purkinje Cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre-Purkinje Cell synapses on Purkinje Cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje Cell synapses using post-mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre-Purkinje Cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje Cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje Cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje Cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje Cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje Cell connections could be of importance in the pathogenesis of essential tremor.
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Purkinje Cell axonal anatomy quantifying morphometric changes in essential tremor versus control brains
Brain, 2013Co-Authors: Rachel Babij, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Growing clinical, neuro-imaging and post-mortem data have implicated the cerebellum as playing an important role in the pathogenesis of essential tremor. Aside from a modest reduction of Purkinje Cells in some post-mortem studies, Purkinje Cell axonal swellings (torpedoes) are present to a greater degree in essential tremor cases than controls. Yet a detailed study of more subtle morphometric changes in the Purkinje Cell axonal compartment has not been undertaken. We performed a detailed morphological analysis of the Purkinje Cell axonal compartment in 49 essential tremor and 39 control brains, using calbindin D28k immunohistochemistry on 100-µm cerebellar cortical vibratome tissue sections. Changes in axonal shape [thickened axonal profiles (P = 0.006), torpedoes (P = 0.038)] and changes in axonal connectivity [axonal recurrent collaterals (P 40 years. In essential tremor cases, thickened axonal profiles, axonal recurrent collaterals and branched axons were 3- to 5-fold more frequently seen on the axons of Purkinje Cells with torpedoes versus Purkinje Cells without torpedoes. We document a range of changes in the Purkinje Cell axonal compartment in essential tremor. Several of these are likely to be compensatory changes in response to Purkinje Cell injury, thus illustrating an important feature of Purkinje Cells, which is that they are relatively resistant to damage and capable of mobilizing a broad range of axonal responses to injury. The extent to which this plasticity of the Purkinje Cell axon is partially neuroprotective or ultimately ineffective at slowing further Cellular changes and Cell death deserves further study in essential tremor.
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quantification of cerebellar hemispheric Purkinje Cell linear density 32 et cases versus 16 controls
Movement Disorders, 2013Co-Authors: Elan D Louis, Etty Cortes, Jean-paul G. Vonsattel, Rachel Babij, Michelle LeeAbstract:Background Although essential tremor (ET) is among the most prevalent neurological diseases, its precise pathogenesis is not understood. Purkinje Cell loss has been observed in some studies and is the focus of interest and debate. Expressing these data as Purkinje Cells/layer length allows one to adjust for the inherent curved nature of the cerebellar folia. Capitalizing on the Essential Tremor Centralized Brain Repository, we quantified Purkinje Cell linear density in cases vs. controls.
Phyllis L Faust - One of the best experts on this subject based on the ideXlab platform.
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Purkinje Cell axonal swellings enhance action potential fidelity and cerebellar function
'Springer Science and Business Media LLC', 2021Co-Authors: Daneck Lang-ouellette, Kim M. Gruver, Amy Smith-dijak, François G. C. Blot, Chloe A. Stewart, Pauline De Vanssay De Blavous, Carter Van Eitrem, Charlotte Rosen, Phyllis L FaustAbstract:Axonal swellings have been found on Purkinje Cell axons in the cerebellum both during development and disease. The authors show that axons with swellings propagate action potentials with higher fidelity than those without and that mice with more axonal swellings learn cerebellar-related tasks better
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Purkinje Cell loss in essential tremor random sampling quantification and nearest neighbor analysis
Movement Disorders, 2016Co-Authors: Matthew Choe, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Introduction Purkinje Cell loss has been documented in some, although not all, postmortem studies of essential tremor. Hence, there is considerable controversy concerning the presence of Purkinje Cell loss in this disease. To date, few studies have been performed. Methods Over the past 8 years, we have assembled 50 prospectively studied cases and 25 age-matched controls; none were reported in our previous large series of 33 essential tremor and 21 controls. In addition to methods used in previous studies, the current study used a random sampling approach to quantify Purkinje Cells along the Purkinje Cell layer with a mean of 217 sites examined in each specimen, allowing for extensive sampling of the Purkinje Cell layer within the section. For the first time, we also quantified the distance between Purkinje Cell bodies—a nearest neighbor analysis. Results In the Purkinje Cell count data collected from fifteen 100 × fields, cases had lower counts than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli; all P < 0.001). Purkinje Cell linear density was also lower in cases than controls (all P < 0.001). Purkinje Cell linear density obtained by random sampling was similarly lower in cases than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli, all P ≤ 0.005). In agreement with the quantitative Purkinje Cell counts, the mean distance from one Purkinje Cell body to another Purkinje Cell body along the Purkinje Cell layer was greater in cases than controls (P = 0.002). Conclusions These data provide support for the neurodegeneration of cerebellar Purkinje Cells in essential tremor. © 2016 International Parkinson and Movement Disorder Society
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reduced Purkinje Cell dendritic arborization and loss of dendritic spines in essential tremor
Brain, 2014Co-Authors: Elan D Louis, Etty Cortes, Jean-paul G. Vonsattel, Rachel Babij, Michelle Lee, Phyllis L FaustAbstract:Based on accumulating post-mortem evidence of abnormalities in Purkinje Cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje Cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje Cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P = 0.01), 465.9 versus 592.5 µm (branch length, P = 0.01), 22.5 versus 29.0 (maximum branch order, P = 0.001), and 165.3 versus 311.7 (number of terminations, P = 0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians = 0.82 versus 1.02 µm−1, P = 0.03). Our demonstration of regressive changes in Purkinje Cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje Cell biology in this disease, which affects multiple neuronal Cellular compartments including their axon, Cell body, dendrites and spines.
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abnormal climbing fibre Purkinje Cell synaptic connections in the essential tremor cerebellum
Brain, 2014Co-Authors: Elan D Louis, Jean-paul G. Vonsattel, Phyllis L Faust, Arnulf H KoeppenAbstract:Structural changes in Purkinje Cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje Cells, and climbing fibre-Purkinje Cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre-Purkinje Cell synapses on Purkinje Cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje Cell synapses using post-mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre-Purkinje Cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje Cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje Cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje Cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje Cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje Cell connections could be of importance in the pathogenesis of essential tremor.
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Purkinje Cell axonal anatomy quantifying morphometric changes in essential tremor versus control brains
Brain, 2013Co-Authors: Rachel Babij, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Growing clinical, neuro-imaging and post-mortem data have implicated the cerebellum as playing an important role in the pathogenesis of essential tremor. Aside from a modest reduction of Purkinje Cells in some post-mortem studies, Purkinje Cell axonal swellings (torpedoes) are present to a greater degree in essential tremor cases than controls. Yet a detailed study of more subtle morphometric changes in the Purkinje Cell axonal compartment has not been undertaken. We performed a detailed morphological analysis of the Purkinje Cell axonal compartment in 49 essential tremor and 39 control brains, using calbindin D28k immunohistochemistry on 100-µm cerebellar cortical vibratome tissue sections. Changes in axonal shape [thickened axonal profiles (P = 0.006), torpedoes (P = 0.038)] and changes in axonal connectivity [axonal recurrent collaterals (P 40 years. In essential tremor cases, thickened axonal profiles, axonal recurrent collaterals and branched axons were 3- to 5-fold more frequently seen on the axons of Purkinje Cells with torpedoes versus Purkinje Cells without torpedoes. We document a range of changes in the Purkinje Cell axonal compartment in essential tremor. Several of these are likely to be compensatory changes in response to Purkinje Cell injury, thus illustrating an important feature of Purkinje Cells, which is that they are relatively resistant to damage and capable of mobilizing a broad range of axonal responses to injury. The extent to which this plasticity of the Purkinje Cell axon is partially neuroprotective or ultimately ineffective at slowing further Cellular changes and Cell death deserves further study in essential tremor.
Elan D Louis - One of the best experts on this subject based on the ideXlab platform.
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Purkinje Cell loss in essential tremor random sampling quantification and nearest neighbor analysis
Movement Disorders, 2016Co-Authors: Matthew Choe, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Introduction Purkinje Cell loss has been documented in some, although not all, postmortem studies of essential tremor. Hence, there is considerable controversy concerning the presence of Purkinje Cell loss in this disease. To date, few studies have been performed. Methods Over the past 8 years, we have assembled 50 prospectively studied cases and 25 age-matched controls; none were reported in our previous large series of 33 essential tremor and 21 controls. In addition to methods used in previous studies, the current study used a random sampling approach to quantify Purkinje Cells along the Purkinje Cell layer with a mean of 217 sites examined in each specimen, allowing for extensive sampling of the Purkinje Cell layer within the section. For the first time, we also quantified the distance between Purkinje Cell bodies—a nearest neighbor analysis. Results In the Purkinje Cell count data collected from fifteen 100 × fields, cases had lower counts than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli; all P < 0.001). Purkinje Cell linear density was also lower in cases than controls (all P < 0.001). Purkinje Cell linear density obtained by random sampling was similarly lower in cases than controls in all three counting criteria (Cell bodies, nuclei, and nucleoli, all P ≤ 0.005). In agreement with the quantitative Purkinje Cell counts, the mean distance from one Purkinje Cell body to another Purkinje Cell body along the Purkinje Cell layer was greater in cases than controls (P = 0.002). Conclusions These data provide support for the neurodegeneration of cerebellar Purkinje Cells in essential tremor. © 2016 International Parkinson and Movement Disorder Society
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reduced Purkinje Cell dendritic arborization and loss of dendritic spines in essential tremor
Brain, 2014Co-Authors: Elan D Louis, Etty Cortes, Jean-paul G. Vonsattel, Rachel Babij, Michelle Lee, Phyllis L FaustAbstract:Based on accumulating post-mortem evidence of abnormalities in Purkinje Cell biology in essential tremor, we hypothesized that regressive changes in dendritic morphology would be apparent in the Purkinje Cell population in essential tremor cases versus age-matched controls. Cerebellar cortical tissue from 27 cases with essential tremor and 27 age-matched control subjects was processed by the Golgi-Kopsch method. Purkinje Cell dendritic anatomy was quantified using a Neurolucida microscopic system interfaced with a motorized stage. In all measures, essential tremor cases demonstrated significant reductions in dendritic complexity compared with controls. Median values in essential tremor cases versus controls were: 5712.1 versus 10 403.2 µm (total dendrite length, P = 0.01), 465.9 versus 592.5 µm (branch length, P = 0.01), 22.5 versus 29.0 (maximum branch order, P = 0.001), and 165.3 versus 311.7 (number of terminations, P = 0.008). Furthermore, the dendritic spine density was reduced in essential tremor cases (medians = 0.82 versus 1.02 µm−1, P = 0.03). Our demonstration of regressive changes in Purkinje Cell dendritic architecture and spines in essential tremor relative to control brains provides additional evidence of a pervasive abnormality of Purkinje Cell biology in this disease, which affects multiple neuronal Cellular compartments including their axon, Cell body, dendrites and spines.
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abnormal climbing fibre Purkinje Cell synaptic connections in the essential tremor cerebellum
Brain, 2014Co-Authors: Elan D Louis, Jean-paul G. Vonsattel, Phyllis L Faust, Arnulf H KoeppenAbstract:Structural changes in Purkinje Cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje Cells, and climbing fibre-Purkinje Cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre-Purkinje Cell synapses on Purkinje Cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje Cell synapses using post-mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre-Purkinje Cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje Cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje Cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje Cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre-Purkinje Cell synapses on the thin Purkinje Cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje Cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje Cell connections could be of importance in the pathogenesis of essential tremor.
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Purkinje Cell axonal anatomy quantifying morphometric changes in essential tremor versus control brains
Brain, 2013Co-Authors: Rachel Babij, Etty Cortes, Jean-paul G. Vonsattel, Phyllis L Faust, Elan D LouisAbstract:Growing clinical, neuro-imaging and post-mortem data have implicated the cerebellum as playing an important role in the pathogenesis of essential tremor. Aside from a modest reduction of Purkinje Cells in some post-mortem studies, Purkinje Cell axonal swellings (torpedoes) are present to a greater degree in essential tremor cases than controls. Yet a detailed study of more subtle morphometric changes in the Purkinje Cell axonal compartment has not been undertaken. We performed a detailed morphological analysis of the Purkinje Cell axonal compartment in 49 essential tremor and 39 control brains, using calbindin D28k immunohistochemistry on 100-µm cerebellar cortical vibratome tissue sections. Changes in axonal shape [thickened axonal profiles (P = 0.006), torpedoes (P = 0.038)] and changes in axonal connectivity [axonal recurrent collaterals (P 40 years. In essential tremor cases, thickened axonal profiles, axonal recurrent collaterals and branched axons were 3- to 5-fold more frequently seen on the axons of Purkinje Cells with torpedoes versus Purkinje Cells without torpedoes. We document a range of changes in the Purkinje Cell axonal compartment in essential tremor. Several of these are likely to be compensatory changes in response to Purkinje Cell injury, thus illustrating an important feature of Purkinje Cells, which is that they are relatively resistant to damage and capable of mobilizing a broad range of axonal responses to injury. The extent to which this plasticity of the Purkinje Cell axon is partially neuroprotective or ultimately ineffective at slowing further Cellular changes and Cell death deserves further study in essential tremor.
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quantification of cerebellar hemispheric Purkinje Cell linear density 32 et cases versus 16 controls
Movement Disorders, 2013Co-Authors: Elan D Louis, Etty Cortes, Jean-paul G. Vonsattel, Rachel Babij, Michelle LeeAbstract:Background Although essential tremor (ET) is among the most prevalent neurological diseases, its precise pathogenesis is not understood. Purkinje Cell loss has been observed in some studies and is the focus of interest and debate. Expressing these data as Purkinje Cells/layer length allows one to adjust for the inherent curved nature of the cerebellar folia. Capitalizing on the Essential Tremor Centralized Brain Repository, we quantified Purkinje Cell linear density in cases vs. controls.
James M Bower - One of the best experts on this subject based on the ideXlab platform.
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3d electron microscopic reconstruction of segments of rat cerebellar Purkinje Cell dendrites receiving ascending and parallel fiber granule Cell synaptic inputs
The Journal of Comparative Neurology, 2009Co-Authors: Angelica V Esquivel, James M BowerAbstract:Growing physiological evidence suggests that there are functional differences between synapses made by the ascending and parallel fiber segments of the granule axon on cerebellar Purkinje Cells. Supporting this view, our previous electron microscopic studies suggested that these synapses also contacted different regions of the Purkinje Cell dendrite, and in particular that ascending segment synapses are made exclusively on the smallest diameter Purkinje Cell dendrites. In the current study we used serial electron microscopic techniques to reconstruct Purkinje Cell dendritic segments up to almost 10 mum in length. Using a combination of anatomical and immunological labeling techniques we identified the ascending or parallel fiber origins of the excitatory synaptic inputs onto dendritic spines, as well as the location of inhibitory synapses made directly on the dendritic shaft. The results confirmed that there are regions of the Purkinje Cell dendrite receiving exclusively ascending or parallel fiber synapses and that ascending segment synapses are only found on small-diameter dendrites. In addition, we describe for the first time small-diameter dendritic regions contacted by both types of excitatory synapses. While our data suggest that the majority of inhibitory inputs to the Purkinje Cell tree are associated with parallel fiber synaptic inputs, we also found inhibitory inputs on dendritic regions with mixed ascending and parallel fiber inputs, or exclusively parallel fiber inputs. The finding that ascending and parallel fiber inputs can be segregated on the Purkinje Cell dendritic tree provides further evidence that these excitatory granule Cell synaptic inputs may be functionally distinct.
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an active membrane model of the cerebellar Purkinje Cell ii simulation of synaptic responses
Journal of Neurophysiology, 1994Co-Authors: E De Schutter, James M BowerAbstract:1. Both excitatory and inhibitory postsynaptic channels were added to a previously described complex compartmental model of a cerebellar Purkinje Cell to examine model responses to synaptic inputs....
Richard Hawkes - One of the best experts on this subject based on the ideXlab platform.
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Purkinje Cell compartmentalization in the cerebellum of the spontaneous mutant mouse dreher
Brain Structure and Function, 2014Co-Authors: Roy V. Sillitoe, Nicholas A. George-jones, Richard HawkesAbstract:The cerebellar morphological phenotype of the spontaneous neurological mutant mouse dreher ( Lmx1a ^ dr - J ) results from Cell fate changes in dorsal midline patterning involving the roof plate and rhombic lip. Positional cloning revealed that the gene Lmx1a , which encodes a LIM homeodomain protein, is mutated in dreher , and is expressed in the developing roof plate and rhombic lip. Loss of Lmx1a causes reduction of the roof plate, an important embryonic signaling center, and abnormal Cell fate specification within the embryonic cerebellar rhombic lip. In adult animals, these defects result in variable, medial fusion of the cerebellar vermis and posterior cerebellar vermis hypoplasia. It is unknown whether deleting Lmx1a results in displacement or loss of specific lobules in the vermis. To distinguish between an ectopic and absent vermis, the expression patterns of two Purkinje Cell-specific compartmentation antigens, zebrin II/aldolase C and the small heat shock protein HSP25 were analyzed in dreher cerebella. The data reveal that despite the reduction in volume and abnormal foliation of the cerebellum, the transverse zones and parasagittal stripe arrays characteristic of the normal vermis are present in dreher , but may be highly distorted. In dreher mutants with a severe phenotype, zebrin II stripes are fragmented and distributed non-symmetrically about the cerebellar midline. We conclude that although Purkinje Cell agenesis or selective Purkinje Cell death may contribute to the dreher phenotype, our data suggest that aberrant anlage patterning and granule Cell development lead to Purkinje Cell ectopia, which ultimately causes abnormal cerebellar architecture in dreher .
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expression of the ip3r1 promoter driven nls lacz transgene in Purkinje Cell parasagittal arrays of developing mouse cerebellum
Journal of Neuroscience Research, 2010Co-Authors: Daisuke Furutama, Noriyuki Morita, Riya Takano, Yukiko Sekine, Tetsushi Sadakata, Yo Shinoda, Kanehiro Hayashi, Yuriko Mishima, Katsuhiko Mikoshiba, Richard HawkesAbstract:: The cerebellar Purkinje Cell monolayer is organized into heterogeneous Purkinje Cell compartments that have different molecular compositions. Here we describe a transgenic mouse line, 1NM13, that shows heterogeneous transgene expression in parasagittal Purkinje Cell arrays. The transgene consists of a nuclear localization signal (nls) fused to the beta-galactosidase (lacZ) composite gene driven by the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R1) gene promoter. IP(3)R1-nls-lacZ transgene expression was detected at a single Purkinje Cell level over the surface of a whole-mount X-gal-stained cerebellum because of nuclear accumulation of the nls-lacZ activity. Developing cerebella of 1NM13 mice showed stripe-like X-gal staining patterns of parasagittal Purkinje Cell subsets. The X-gal stripe pattern was likely determined by an intrinsic property as early as E15 and showed increasing complexity with cerebellar development. The X-gal stripe pattern was reminiscent of, but not identical to, the stripe pattern of zebrin II immunoreactivity. We designated the symmetrical X-gal-positive (transgene-positive, Tg(+)) Purkinje Cell stripes about the midline as vermal Tg1(+), Tg2(a, b)(+) and Tg3(a, b)(+) stripes and hemispheric Tg4(a, b)(+), Tg5(a, b)(+), Tg6(a, b, c)(+), and Tg7(a, b)(+) stripes, where a, b, and c indicate substripes. We also assigned three parafloccular substripes Tg8(a, b, c)(+). The boundaries of X-gal stripes at P5 were consistent with raphes in the Purkinje Cell layer through which granule Cells migrate, suggesting a possible association of the X-gal stripes with raphe formation. Our results indicate that 1NM13 is a good mouse model with a reproducible and clear marker for the compartmentalization of Purkinje Cell arrays.
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complementary stripes of phospholipase cβ3 and cβ4 expression by Purkinje Cell subsets in the mouse cerebellum
The Journal of Comparative Neurology, 2006Co-Authors: Justyna R Sarna, Masahiko Watanabe, Hassan Marzban, Richard HawkesAbstract:Transverse boundaries divide the cerebellar cortex into four transverse zones, and within each zone the cortex is further subdivided into a symmetrical array of parasagittal stripes. Several molecules believed to mediate long-term depression at the parallel fiber–Purkinje Cell synapse are known to be expressed in stripes. We have therefore explored the distributions of phospholipase Cβ3 and phospholipase Cβ4, key components in the transduction of type 1 metabotropic glutamate receptor-mediated responses. The data reveal that both phospholipase Cβ isotypes are expressed strongly in the mouse cerebellum in subsets of Purkinje Cells. The two distributions are distinct and largely nonoverlapping. The pattern of phospholipase Cβ3 expression is unique, revealing stripes in three of the four transverse zones and a uniform distribution in the fourth. In contrast, phospholipase Cβ4 appears to be confined largely to the Purkinje Cells that are phospholipase Cβ3-negative. PLCβ3 is restricted to the zebrin II-immunopositive Purkinje Cell subset. Not all zebrin II-immunoreactive Purkinje Cells express PLCβ3: in lobules IX and X it is restricted to that zebrin II-immunopositive subset that also expresses the small heat shock protein HSP25. PLCβ4 expression is restricted to, and coextensive with, the zebrin II-immunonegative Purkinje Cell subset. These nonoverlapping expression patterns suggest that long-term depression may be manifested differently between cerebellar modules. J. Comp. Neurol. 496:303–313, 2006. © 2006 Wiley-Liss, Inc.
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patterned Purkinje Cell death in the cerebellum
Progress in Neurobiology, 2003Co-Authors: Justyna R Sarna, Richard HawkesAbstract:The object of this review is to assemble much of the literature concerning Purkinje Cell death in cerebellar pathology and to relate this to what is now known about the complex topography of the cerebellar cortex. A brief introduction to Purkinje Cells, and their regionalization is provided, and then the data on Purkinje Cell death in mouse models and, where appropriate, their human counterparts, have been arranged according to several broad categories—naturally-occurring and targeted mutations leading to Purkinje Cell death, Purkinje Cell death due to toxins, Purkinje Cell death in ischemia, Purkinje Cell death in infection and in inherited disorders, etc. The data reveal that cerebellar Purkinje Cell death is much more topographically complex than is usually appreciated.
