-
Brain Pathology (Zurich, Switzerland) Sep 2021Purkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties,...
Purkinje cells are the primary processing units of the cerebellar cortex and display molecular heterogeneity that aligns with differences in physiological properties, projection patterns, and susceptibility to disease. In particular, multiple mouse models that feature Purkinje cell degeneration are characterized by incomplete and patterned Purkinje cell degeneration, suggestive of relative sparing of Purkinje cell subpopulations, such as those expressing Aldolase C/zebrinII (AldoC) or residing in the vestibulo-cerebellum. Here, we investigated a well-characterized Purkinje cell-specific mouse model for spinocerebellar ataxia type 1 (SCA1) that expresses human ATXN1 with a polyQ expansion (82Q). Our pathological analysis confirms previous findings that Purkinje cells of the vestibulo-cerebellum, i.e., the flocculonodular lobes, and crus I are relatively spared from key pathological hallmarks: somatodendritic atrophy, and the appearance of p62/SQSTM1-positive inclusions. However, immunohistological analysis of transgene expression revealed that spared Purkinje cells do not express mutant ATXN1 protein, indicating the sparing of Purkinje cells can be explained by an absence of transgene expression. Additionally, we found that Purkinje cells in other cerebellar lobules that typically express AldoC, not only display severe pathology but also show loss of AldoC expression. The relatively preserved flocculonodular lobes and crus I showed a substantial fraction of Purkinje cells that expressed the mutant protein and displayed pathology as well as loss of AldoC expression. Despite considerable pathology in these lobules, behavioral analyses demonstrated a relative sparing of related functions, suggestive of sufficient functional cerebellar reserve. Together, the data indicate that mutant ATXN1 affects both AldoC-positive and AldoC-negative Purkinje cells and disrupts normal parasagittal AldoC expression in Purkinje cells. Our results show that, in a mouse model otherwise characterized by widespread Purkinje cell degeneration, sparing of specific subpopulations is sufficient to maintain normal performance of specific behaviors within the context of the functional, modular map of the cerebellum.
Topics: Animals; Ataxin-1; Behavior, Animal; Cerebellum; Disease Models, Animal; Mice; Motor Activity; Peptides; Purkinje Cells
PubMed: 33724582
DOI: 10.1111/bpa.12946 -
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 -
Cerebellum (London, England) Jun 2022Gerbrandus Jelgersma published extensively on the (pathological) anatomy of the cerebellum between 1886 and 1934. Based on his observations on the double innervation of...
Gerbrandus Jelgersma published extensively on the (pathological) anatomy of the cerebellum between 1886 and 1934. Based on his observations on the double innervation of the Purkinje cells, he formulated a hypothesis on the function of the cerebellum. Both afferent systems of the cerebellum, the mossy fiber-parallel fiber system and the climbing fibers terminate on the Purkinje cell dendrites. According to Jelgersma, the mossy fiber-parallel fiber system is derived from the pontine nuclei and the inferior olive, and would transmit the movement images derived from the cerebral cortex. Spinocerebellar climbing fibers would transmit information about the execution of the movement. When the Purkinje cell compares these inputs and notices a difference between instruction and execution, it sends a correction through the descending limb of the superior cerebellar peduncle to the anterior horn cells. Jelgersma postulates that this cerebro-cerebellar coordination system shares plasticity with other nervous connections because nerve cell dendritic protrusions possess what he called amoeboid mobility: dendritic protrusions can be extended or retracted and are so able to create new connections or to abolish them. Jelgersma's theories are discussed against the background of more recent theories of cerebellar function that, similarly, are based on the double innervation of the Purkinje cells. The amoeboid hypothesis is traced to its roots in the late nineteenth century.
Topics: Cerebellar Cortex; Cerebellum; Neurons; Olivary Nucleus; Purkinje Cells
PubMed: 34383219
DOI: 10.1007/s12311-021-01273-4 -
Neurobiology of Disease Jul 2023Mitochondrial deficits have been observed in animal models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and in patient-derived fibroblasts. We...
Mitochondrial deficits have been observed in animal models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and in patient-derived fibroblasts. We investigated whether mitochondrial function could be restored in Sacs mice, a mouse model of ARSACS, using the mitochondrial-targeted antioxidant ubiquinone MitoQ. After 10weeks of chronic MitoQ administration in drinking water, we partially reversed motor coordination deficits in Sacs mice but did not affect litter-matched wild-type control mice. MitoQ administration led to a restoration of superoxide dismutase 2 (SOD2) in cerebellar Purkinje cell somata without altering Purkinje cell firing deficits. Purkinje cells in anterior vermis of Sacs mice normally undergo cell death in ARSACS; however, Purkinje cells numbers were elevated after chronic MitoQ treatment. Furthermore, Purkinje cell innervation of target neurons in the cerebellar nuclei of Sacs mice was also partially restored with MitoQ treatment. Our data suggest that MitoQ is a potential therapeutic treatment for ARSACS and that it improves motor coordination via increasing cerebellar Purkinje cell mitochondria function and reducing Purkinje cell death.
Topics: Animals; Mice; Purkinje Cells; Antioxidants; Ataxia; Cerebellar Ataxia; Mitochondria; Disease Models, Animal
PubMed: 37209925
DOI: 10.1016/j.nbd.2023.106157 -
Cerebellum (London, England) Dec 2022This paper presents a model of learning by the cerebellar circuit. In the traditional and dominant learning model, training teaches finely graded parallel fibre synaptic...
This paper presents a model of learning by the cerebellar circuit. In the traditional and dominant learning model, training teaches finely graded parallel fibre synaptic weights which modify transmission to Purkinje cells and to interneurons that inhibit Purkinje cells. Following training, input in a learned pattern drives a training-modified response. The function is that the naive response to input rates is displaced by a learned one, trained under external supervision. In the proposed model, there is no weight-controlled graduated balance of excitation and inhibition of Purkinje cells. Instead, the balance has two functional states-a switch-at synaptic, whole cell and microzone level. The paper is in two parts. The first is a detailed physiological argument for the synaptic learning function. The second uses the function in a computational simulation of pattern memory. Against expectation, this generates a predictable outcome from input chaos (real-world variables). Training always forces synaptic weights away from the middle and towards the limits of the range, causing them to polarise, so that transmission is either robust or blocked. All conditions teach the same outcome, such that all learned patterns receive the same, rather than a bespoke, effect on transmission. In this model, the function of learning is gating-that is, to select patterns that trigger output merely, and not to modify output. The outcome is memory-operated gate activation which operates a two-state balance of weight-controlled transmission. Group activity of parallel fibres also simultaneously contains a second code contained in collective rates, which varies independently of the pattern code. A two-state response to the pattern code allows faithful, and graduated, control of Purkinje cell firing by the rate code, at gated times.
Topics: Cerebellum; Purkinje Cells; Learning; Axons; Interneurons
PubMed: 34757585
DOI: 10.1007/s12311-021-01325-9 -
Translational Psychiatry Jul 2014The p75 neurotrophin receptor (p75NTR) is normally expressed in cerebellar Purkinje cells throughout the lifespan. Children with autism spectrum behavior exhibit...
The p75 neurotrophin receptor (p75NTR) is normally expressed in cerebellar Purkinje cells throughout the lifespan. Children with autism spectrum behavior exhibit apparent cerebellar Purkinje cell loss. Cerebellar transcriptome changes seen in the murine prenatal valproate exposure model of autism include all of the proteins known to constitute the p75NTR interactome. p75NTR is a modulator of cytoplasmic and mitochondrial redox potential, and others have suggested that aberrant response to oxidant stress has a major role in the pathogenesis of autism. We have created Purkinje cell-selective p75NTR knockout mice that are the progeny of hemizygous Cre-Purkinje cell protein 2 C57Bl mice and p75NTR floxed C57Bl mice. These Cre-loxP mice exhibit complete knockout of p75NTR in ~50% of the cerebellar Purkinje cells. Relative to Cre-only mice and wild-type C57Bl mice, this results in a behavioral phenotype characterized by less allogrooming of (P<0.05; one-way analysis of variance) and socialization or fighting with (each P<0.05) other mice; less (1.2-fold) non-ambulatory exploration of their environment than wild-type (P<0.01) or Cre only (P<0.01) mice; and almost twofold more stereotyped jumping behavior than wild-type (P<0.05) or Cre (P<0.02) mice of the same strain. Wild-type mice have more complex dendritic arborization than Cre-loxP mice, with more neurites per unit area (P<0.025, Student's t-test), more perpendicular branches per unit area (P<0.025) and more short branches/long neurite (P<0.0005). Aberrant developmental regulation of expression of p75NTR in cerebellar Purkinje cells may contribute to the pathogenesis of autism.
Topics: Agonistic Behavior; Animals; Autistic Disorder; Disease Models, Animal; Gene Expression; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Purkinje Cells; Receptors, Nerve Growth Factor; Socialization; Stereotyped Behavior; Transcriptome
PubMed: 25072321
DOI: 10.1038/tp.2014.55 -
Neurotherapeutics : the Journal of the... Jul 2021Oleoylethanolamide (OEA) is an endocannabinoid that has been proposed to prevent neuronal damage and neuroinflammation. In this study, we evaluated the effects of OEA on...
Oleoylethanolamide (OEA) is an endocannabinoid that has been proposed to prevent neuronal damage and neuroinflammation. In this study, we evaluated the effects of OEA on the disruption of both cerebellar structure and physiology and on the behavior of Purkinje cell degeneration (PCD) mutant mice. These mice exhibit cerebellar degeneration, displaying microtubule alterations that trigger the selective loss of Purkinje cells and consequent behavioral impairments. The effects of different doses (1, 5, and 10 mg/kg, i.p.) and administration schedules (chronic and acute) of OEA were assessed at the behavioral, histological, cellular, and molecular levels to determine the most effective OEA treatment regimen. Our in vivo results demonstrated that OEA treatment prior to the onset of the preneurodegenerative phase prevented morphological alterations in Purkinje neurons (the somata and dendritic arbors) and decreased Purkinje cell death. This effect followed an inverted U-shaped time-response curve, with acute administration on postnatal day 12 (10 mg/kg, i.p.) being the most effective treatment regimen tested. Indeed, PCD mice that received this specific OEA treatment regimen showed improvements in motor, cognitive and social functions, which were impaired in these mice. Moreover, these in vivo neuroprotective effects of OEA were mediated by the PPARα receptor, as pretreatment with the PPARα antagonist GW6471 (2.5 mg/kg, i.p.) abolished them. Finally, our in vitro results suggested that the molecular effect of OEA was related to microtubule stability and structure since OEA administration normalized some alterations in microtubule features in PCD-like cells. These findings provide strong evidence supporting the use of OEA as a pharmacological agent to limit severe cerebellar neurodegenerative processes.
Topics: Animals; Cell Death; Cells, Cultured; Cerebellar Diseases; Disease Models, Animal; Endocannabinoids; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Transgenic; Neurodegenerative Diseases; Oleic Acids; Purkinje Cells
PubMed: 33829414
DOI: 10.1007/s13311-021-01044-3 -
Movement Disorders : Official Journal... Mar 2016Purkinje cell loss has been documented in some, although not all, postmortem studies of essential tremor. Hence, there is considerable controversy concerning the...
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.
Topics: Aged; Aged, 80 and over; Autopsy; Cell Count; Cell Death; Cerebellum; Essential Tremor; Female; Humans; Male; Neurodegenerative Diseases; Purkinje Cells
PubMed: 26861543
DOI: 10.1002/mds.26490 -
ELife Apr 2022The ability to accurately control our posture and perceive our spatial orientation during self-motion requires knowledge of the motion of both the head and body....
The ability to accurately control our posture and perceive our spatial orientation during self-motion requires knowledge of the motion of both the head and body. However, while the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the integration of vestibular and neck proprioceptive inputs is necessary to transform vestibular information into the body-centric reference frame required for postural control. The anterior vermis of the cerebellum is thought to play a key role in this transformation, yet how its Purkinje cells transform multiple streams of sensory information into an estimate of body motion remains unknown. Here, we recorded the activity of individual anterior vermis Purkinje cells in alert monkeys during passively applied whole-body, body-under-head, and head-on-body rotations. Most Purkinje cells dynamically encoded an intermediate representation of self-motion between head and body motion. Notably, Purkinje cells responded to both vestibular and neck proprioceptive stimulation with considerable heterogeneity in their response dynamics. Furthermore, their vestibular responses were tuned to head-on-body position. In contrast, targeted neurons in the deep cerebellar nuclei are known to unambiguously encode either head or body motion across conditions. Using a simple population model, we established that combining responses of~40-50 Purkinje cells could explain the responses of these deep cerebellar nuclei neurons across all self-motion conditions. We propose that the observed heterogeneity in Purkinje cell response dynamics underlies the cerebellum's capacity to compute the dynamic representation of body motion required to ensure accurate postural control and perceptual stability in our daily lives.
Topics: Animals; Cerebellum; Head Movements; Macaca; Motion; Purkinje Cells
PubMed: 35467528
DOI: 10.7554/eLife.75018 -
Nature Communications Mar 2023Dopamine has a significant role in motor and cognitive function. The dopaminergic pathways originating from the midbrain have received the most attention; however, the...
Dopamine has a significant role in motor and cognitive function. The dopaminergic pathways originating from the midbrain have received the most attention; however, the relevance of the cerebellar dopaminergic system is largely undiscovered. Here, we show that the major cerebellar astrocyte type Bergmann glial cells express D1 receptors. Dopamine can be synthesized in Purkinje cells by cytochrome P450 and released in an activity-dependent fashion. We demonstrate that activation of D1 receptors induces membrane depolarization and Ca release from the internal store. These astrocytic activities in turn modify Purkinje cell output by altering its excitatory and inhibitory synaptic input. Lastly, we show that conditional knockout of D1 receptors in Bergmann glial cells results in decreased locomotor activity and impaired social activity. These results contribute to the understanding of the molecular, cellular, and circuit mechanisms underlying dopamine function in the cerebellum, revealing a critical role for the cerebellar dopaminergic system in motor and social behavior.
Topics: Purkinje Cells; Astrocytes; Dopamine; Cerebellum; Neuroglia
PubMed: 36959176
DOI: 10.1038/s41467-023-37319-w