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Cerebellum (London, England) Sep 2011The Lurcher mutant mouse is characterized by its ataxic gait and loss of cerebellar Purkinje cells and their afferents, granule cells and olivary neurons, during the... (Review)
Review
The Lurcher mutant mouse is characterized by its ataxic gait and loss of cerebellar Purkinje cells and their afferents, granule cells and olivary neurons, during the first weeks of postnatal development. For the 50 years since its discovery, the heterozygous Lurcher mutant has served as an important model system for studying neuron-target interactions in the developing cerebellum and cerebellar function. The identification of the Lurcher (Lc) gene over 10 years ago as a gain-of-function mutation in the δ2 glutamate receptor (GluRδ2) led to extensive studies of cell death mechanisms in the Lc/+ cerebellum. The advantage of this model system is that GluRδ2(+) receptors and GluRδ2(Lc) channels are expressed predominantly in Purkinje cells, making it possible to study the effects of a well-characterized leak current in a well-defined cell type during a critical phase of neuronal development. Yet there is still controversy surrounding the mechanisms of neuronal death in Lc/+ Purkinje cells with competing hypotheses for necrotic, apoptotic, and autophagic cell death pathways as a consequence of the excitotoxic stress caused by the GluRδ2(Lc) leak current. The goal of this review is to summarize recent studies that critically test the role of various cell death pathways in Lc/+ Purkinje cell degeneration with respect to evidence for the molecular heterogeneity of Purkinje cells. We propose that the expression of putative survival factors, such as heat shock proteins, in a subset of cerebellar Purkinje cells may affect cell death pathways and account for the pattern and diverse mechanisms of Lc/+ Purkinje degeneration.
Topics: Animals; Animals, Newborn; Apoptosis; Cell Survival; Cerebellum; Heat-Shock Proteins; Mice; Mice, Neurologic Mutants; Models, Neurological; Molecular Chaperones; Neoplasm Proteins; Purkinje Cells
PubMed: 21104177
DOI: 10.1007/s12311-010-0231-4 -
Neural Networks : the Official Journal... Nov 2013The Purkinje cells in the cerebellum are unique neurons that generate local and global Ca(2+) signals in response to two types of excitatory inputs, parallel fiber and... (Review)
Review
The Purkinje cells in the cerebellum are unique neurons that generate local and global Ca(2+) signals in response to two types of excitatory inputs, parallel fiber and climbing fiber, respectively. The spatiotemporal distribution and interaction of these synaptic inputs produce complex patterns of Ca(2+) dynamics in the Purkinje cell dendrites. The Ca(2+) signals originate from Ca(2+) influx through voltage-gated Ca(2+) channels and Ca(2+) release from intracellular stores that are mediated by the metabotropic glutamate receptor signaling pathway. These Ca(2+) signals are essential for the induction of various forms of synaptic plasticity and for controlling the input-output relationship of Purkinje cells. In this article we review Ca(2+) signaling in Purkinje cell dendrites.
Topics: Calcium Signaling; Cerebellum; Dendrites; Humans; Neuronal Plasticity; Purkinje Cells
PubMed: 22985934
DOI: 10.1016/j.neunet.2012.08.001 -
Neuroscience Letters Jan 2019The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it... (Review)
Review
The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.
Topics: Animals; Cerebellar Diseases; Cerebellum; Humans; Purkinje Cells
PubMed: 29746896
DOI: 10.1016/j.neulet.2018.05.013 -
Cerebellum (London, England) 2006This review is devoted to Purkinje cell death occurring during development and in spontaneous cerebellar mutations of the mouse. We first present evidence in favor of an... (Review)
Review
This review is devoted to Purkinje cell death occurring during development and in spontaneous cerebellar mutations of the mouse. We first present evidence in favor of an apoptotic developmental Purkinje cell death. Then, the different types of Purkinje cell degeneration occurring in mutant mice primarily affecting this neuronal population (nervous, purkinje cell degeneration, Lurcher, toppler, and woozy) are described and discussed. In addition, we show, by reporting new data, that cell death in tambaleante mutant mice can be related to autophagy. Last, we discuss the fact that the cell death pathways in mutant mice are more complex than the three types of developmental death generally described (apoptosis, autophagy, necrosis), since they share often characteristics of more than one type of these developmental cell deaths, particularly autophagy and apoptosis.
Topics: Animals; Apoptosis; Autophagy; Cerebellar Cortex; Disease Models, Animal; Mice; Mice, Neurologic Mutants; Necrosis; Nerve Degeneration; Purkinje Cells
PubMed: 16818391
DOI: 10.1080/14734220600699373 -
Behavioural Brain Research Oct 2013The cerebellum consists of the cerebellar cortex and the cerebellar nuclei. Although the basic neuronal circuitry of the cerebellar cortex is uniform everywhere,... (Review)
Review
The cerebellum consists of the cerebellar cortex and the cerebellar nuclei. Although the basic neuronal circuitry of the cerebellar cortex is uniform everywhere, anatomical data demonstrate that the input and output relationships of the cortex are spatially segregated between different cortical areas, which suggests that there are functional distinctions between these different areas. Perturbation of cerebellar cortical functions in a spatially restricted fashion is thus essential for investigating the distinctions among different cortical areas. In the cerebellar cortex, Purkinje cells are the sole output neurons that send information to downstream cerebellar and vestibular nuclei. Therefore, selective manipulation of Purkinje cell activities, without disturbing other neuronal types and passing fibers within the cortex, is a direct approach to spatially restrict the effects of perturbations. Although this type of approach has for many years been technically difficult, recent advances in optogenetics now enable selective activation or inhibition of Purkinje cell activities, with high temporal resolution. Here we discuss the effectiveness of using Purkinje cell-specific optogenetic approaches to elucidate the functions of local cerebellar cortex regions. We also discuss what improvements to current methods are necessary for future investigations of cerebellar functions to provide further advances.
Topics: Animals; Brain Mapping; Cerebellum; Optogenetics; Purkinje Cells
PubMed: 23623886
DOI: 10.1016/j.bbr.2013.04.019 -
Brain Pathology (Zurich, Switzerland) Nov 2015Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter...
Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly. As Purkinje cell axons are the sole output of the cerebellar cortex, understanding pathologic processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia. We studied pathologic changes occurring within Purkinje cells of the cerebellum. Using immunohistochemic techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament. We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex. These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.
Topics: Aged; Aged, 80 and over; Axons; Cell Death; Cerebellum; Cohort Studies; Female; Fluorescent Antibody Technique; Humans; Intermediate Filaments; Male; Middle Aged; Multiple Sclerosis; Phosphorylation; Purkinje Cells
PubMed: 25411024
DOI: 10.1111/bpa.12230 -
Cerebellum (London, England) 2006Purkinje cells, the first nerve cells to be described, are still one of the most interesting and useful experimental models to investigate different aspects of neural...
Purkinje cells, the first nerve cells to be described, are still one of the most interesting and useful experimental models to investigate different aspects of neural function. This special issue of The Cerebellum is dedicated to this very special neuron and contains a number of articles covering different topics of Purkinje cell research, from developmental neurobiology to neurophysiology and neuropathology. More than 150 years after their discovery, Purkinje cells remain one of the most popular neurons in the neuroscience community.
Topics: Animals; Cell Biology; Humans; Learning; Models, Biological; Neurosciences; Purkinje Cells; Synaptic Transmission
PubMed: 16818381
DOI: 10.1080/14734220600788903 -
Neuroscience Letters Jan 2022Opioid receptors play important roles in, among others, learning and memory, emotional responses, addiction, and pain. In recent years, the cerebellum has received...
Opioid receptors play important roles in, among others, learning and memory, emotional responses, addiction, and pain. In recent years, the cerebellum has received increasing attention for its role in non-motor functions. The Purkinje cell (PC) is the only efferent neuron in the cerebellar cortex, and receives glutamatergic synaptic inputs from the parallel fibers (PF) formed by the axons of granule cells. Studies have shown that opioid receptors are expressed during the development of cerebellar cells. However, the distribution of opioid receptors, their subtypes in cerebellar PF-PC synapses, and their effects on synaptic transmission remain unclear. To examine these questions, we used whole-cell patch clamp recordings and pharmacological methods to determine the effects of activating three different opioid receptor subtypes on synaptic transmission at PF-PC synapses. In the presence of picrotoxin, mouse cerebellar slices were perfused with agonists or blockers of different opioid receptor subtypes, and the changes in excitatory postsynaptic currents (EPSCs) were examined. Both agonists of µ-opioid receptors (MOR) and δ-opioid receptors (DOR) significantly reduced the amplitude and area under the curve of PF-PC EPSCs in a concentration-dependent manner, accompanied by an increase in the paired-pulsed ratio (PPR). These effects could be blocked by respective receptor antagonists. In contrast, no significant changes were found after the application of κ-opioid receptor (KOR) agonists. In conclusion, MOR and DOR are present at the axon terminals of PF in the mouse cerebellar cortex, whereas no or negligible amounts of KOR are found. Activation of MOR and DOR regulates PF-PC synaptic transmission via inhibition of glutamate (Glu) release in cerebellar cortex in mice. We also found that endogenous opioid peptides are present in PF-PC synapses of mouse cerebellum, which also can inhibit the release of Glu.
Topics: Animals; Excitatory Postsynaptic Potentials; Glutamic Acid; Male; Mice; Purkinje Cells; Receptors, Opioid; Synaptic Transmission
PubMed: 34808268
DOI: 10.1016/j.neulet.2021.136356 -
Neuroscience Sep 2009The peculiar shape and disposition of Purkinje cell (PC) dendrites, planar and highly branched, offers an optimal model to analyze cellular and molecular regulators for... (Review)
Review
The peculiar shape and disposition of Purkinje cell (PC) dendrites, planar and highly branched, offers an optimal model to analyze cellular and molecular regulators for the acquisition of neuronal dendritic trees. During the first 2 weeks after the end of the proliferation period, PCs undergo a 2-phase remodeling process of their dendrites. The first phase consists in the complete retraction of the primitive but extensive dendritic tree, together with the formation of multiple filopodia-like processes arising from the cell body. In the second phase, there is a progressive disappearance of the somatic processes along with rapid growth and branching of the mature dendrite. Mature Purkinje cell dendrites bear two types of spiny protrusions, named spine and thorn. The spines are numerous, elongated, located at the distal dendritic compartment and form synapses with parallel fibers, whereas the thorns are shorter, rounded, emerge from the proximal compartment and synapse with climbing fibers. Different culture models and mutant mice analyses suggest the identification of intrinsic versus extrinsic determinants of the Purkinje cell dendritic development. The early phase of dendritic remodeling might be cell autonomous and regulated by specific transcription factors such as retinoid-related orphan receptor alpha (RORalpha). Afferent fibers, trophic factors and hormones regulate the orientation and growth of the mature dendritic tree contributing, with still unknown intrinsic factors, to sculpt its general architecture. The formation of spines appears as an intrinsic phenomenon independent of their presynaptic partner, the parallel fibers, and confined to the distal compartment by inhibitory influences of the climbing fibers along the proximal compartment.
Topics: Animals; Cell Polarity; Cerebellum; Dendrites; Humans; Nerve Fibers; Purkinje Cells
PubMed: 19166910
DOI: 10.1016/j.neuroscience.2008.12.035 -
Neurochemistry International Jul 1994In the adult brain there is a high degree of plasticity which is documented here for climbing fibre terminal arborization impinging upon the proximal Purkinje cell... (Review)
Review
In the adult brain there is a high degree of plasticity which is documented here for climbing fibre terminal arborization impinging upon the proximal Purkinje cell dendrites. Such an arborization presents a more distal compartment, including 90% of branches and varicosities, whose integrity depends on the target and a more proximal compartment which survives to target degeneration. The same terminal arborization enlarges its territory of innervation through collateral sprouting when nearby Purkinje cells are deprived of their climbing fibres or when embryonic Purkinje cells are placed on the surface of an intact cerebellum. In the latter case axonal elongation occurs in the absence of degeneration products and of macrophage/microglia or astrocyte activation. In addition, the embryonic Purkinje cells are able to invade the intact host molecular layer where they develop dendritic arbours which become also innervated by climbing fibre collaterals.
Topics: Aging; Animals; Humans; Models, Biological; Nerve Fibers; Neuronal Plasticity; Purkinje Cells
PubMed: 7950976
DOI: 10.1016/0197-0186(94)90058-2