Calbindin in Cerebellar Purkinje Cells Is a Critical Determinant of the Precision of Motor Coordination

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

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Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512915112 ◽

2015 ◽

Vol 112 (50) ◽

pp. 15474-15479 ◽

Cited By ~ 11

Author(s):

Liang Zhou ◽

Dong Yang ◽

De-Juan Wang ◽

Ya-Jun Xie ◽

Jia-Huan Zhou ◽

...

Keyword(s):

Cell Fate ◽

Purkinje Cells ◽

Glutamate Receptor ◽

Motor Coordination ◽

Metabotropic Glutamate Receptor ◽

Constitutive Expression ◽

Metabotropic Glutamate ◽

Associated Proteins ◽

Cerebellar Purkinje Cells

Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber–PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.

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Subchronic Administration of High-Dose Sodium Fluoride Causes Deficits in Cerebellar Purkinje Cells But Not Motor Coordination of Rats

Biological Trace Element Research ◽

10.1007/s12011-018-1420-0 ◽

2018 ◽

Vol 188 (2) ◽

pp. 424-433 ◽

Cited By ~ 3

Author(s):

Fitriani Agustina ◽

Zaenal Muttaqien Sofro ◽

Ginus Partadiredja

Keyword(s):

Purkinje Cells ◽

Sodium Fluoride ◽

Motor Coordination ◽

High Dose ◽

Cerebellar Purkinje Cells

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The Knockout of Secretin in Cerebellar Purkinje Cells Impairs Mouse Motor Coordination and Motor Learning

Neuropsychopharmacology ◽

10.1038/npp.2013.344 ◽

2013 ◽

Vol 39 (6) ◽

pp. 1460-1468 ◽

Cited By ~ 20

Author(s):

Li Zhang ◽

Sookja Kim Chung ◽

Billy Kwok Chong Chow

Keyword(s):

Motor Learning ◽

Purkinje Cells ◽

Motor Coordination ◽

Cerebellar Purkinje Cells

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High dosage of monosodium glutamate causes deficits of the motor coordination and the number of cerebellar Purkinje cells of rats

Human & Experimental Toxicology ◽

10.1177/0960327115572706 ◽

2015 ◽

Vol 34 (11) ◽

pp. 1171-1179 ◽

Cited By ~ 6

Author(s):

D Prastiwi ◽

A Djunaidi ◽

G Partadiredja

Keyword(s):

Purkinje Cells ◽

Chloride Solution ◽

Wistar Rats ◽

Motor Coordination ◽

Monosodium Glutamate ◽

Male Rats ◽

The World ◽

Cerebellar Purkinje Cells ◽

Flavoring Agent ◽

Different Doses

Monosodium glutamate (MSG) has been widely used throughout the world as a flavoring agent of food. However, MSG at certain dosages is also thought to cause damage to many organs, including cerebellum. This study aimed at investigating the effects of different doses of MSG on the motor coordination and the number of Purkinje cells of the cerebellum of Wistar rats. A total of 24 male rats aged 4 to 5 weeks were divided into four groups, namely, control (C), T2.5, T3, and T3.5 groups, which received intraperitoneal injection of 0.9% sodium chloride solution, 2.5 mg/g body weight (bw) of MSG, 3.0 mg/g bw of MSG, and 3.5 mg/g bw of MSG, respectively, for 10 consecutive days. The motor coordination of the rats was examined prior and subsequent to the treatment. The number of cerebellar Purkinje cells was estimated using physical fractionator method. It has been found that the administration of MSG at a dosage of 3.5 mg/g bw, but not at lower dosages, caused a significant decrease of motor coordination and the estimated total number of Purkinje cells of rats. There was also a significant correlation between motor coordination and the total number of Purkinje cells.

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Modulatory Effects of Monoamines and Perineuronal Nets on Output of Cerebellar Purkinje Cells

Frontiers in Neural Circuits ◽

10.3389/fncir.2021.661899 ◽

2021 ◽

Vol 15 ◽

Author(s):

Moritoshi Hirono ◽

Fuyuki Karube ◽

Yuchio Yanagawa

Keyword(s):

Purkinje Cells ◽

Motor Coordination ◽

Gaba Release ◽

Cerebellar Nuclei ◽

Brain Regions ◽

Perineuronal Nets ◽

Gabaergic Transmission ◽

Neural Connections ◽

Brain Functions ◽

Cerebellar Purkinje Cells

Classically, the cerebellum has been thought to play a significant role in motor coordination. However, a growing body of evidence for novel neural connections between the cerebellum and various brain regions indicates that the cerebellum also contributes to other brain functions implicated in reward, language, and social behavior. Cerebellar Purkinje cells (PCs) make inhibitory GABAergic synapses with their target neurons: other PCs and Lugaro/globular cells via PC axon collaterals, and neurons in the deep cerebellar nuclei (DCN) via PC primary axons. PC-Lugaro/globular cell connections form a cerebellar cortical microcircuit, which is driven by serotonin and noradrenaline. PCs’ primary outputs control not only firing but also synaptic plasticity of DCN neurons following the integration of excitatory and inhibitory inputs in the cerebellar cortex. Thus, strong PC-mediated inhibition is involved in cerebellar functions as a key regulator of cerebellar neural networks. In this review, we focus on physiological characteristics of GABAergic transmission from PCs. First, we introduce monoaminergic modulation of GABAergic transmission at synapses of PC-Lugaro/globular cell as well as PC-large glutamatergic DCN neuron, and a Lugaro/globular cell-incorporated microcircuit. Second, we review the physiological roles of perineuronal nets (PNNs), which are organized components of the extracellular matrix and enwrap the cell bodies and proximal processes, in GABA release from PCs to large glutamatergic DCN neurons and in cerebellar motor learning. Recent evidence suggests that alterations in PNN density in the DCN can regulate cerebellar functions.

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Ultrastorcture of Cerebellar Purkinje Cells in Rats Subjected To Partial Global Cerebral Ischemia

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120060 ◽

1985 ◽

Vol 43 ◽

pp. 674-675

Author(s):

R.V.W. Dimlich ◽

M.H. Biros

Keyword(s):

Cerebral Ischemia ◽

Purkinje Cells ◽

Cell Types ◽

Microscopic Level ◽

Global Cerebral Ischemia ◽

Light Microscopic Level ◽

Cerebellar Damage ◽

Cerebellar Injury ◽

Cerebellar Purkinje Cells ◽

Cell Changes

In severe cerebral ischemia, Purkinje cells of the cerebellum are one of the cell types most vulnerable to anoxic damage. In the partial (forebrain) global ischemic (PGI) model of the rat, Paljärvi noted at the light microscopic level that cerebellar damage is inconsistant and when present, milder than in the telencephalon, diencephalon and rostral brain stem. Cerebellar injury was observed in 3 of 4 PGI rats following 5 minutes of reperfusion but in none of the rats after 90 min of reperfusion. To evaluate a time between these two extremes (5 and 90 min), the present investigation used the PGI model to study the effects of ischemia on the ultrastructure of cerebellar Purkinje cells in rats that were sacrificed after 30 min of reperfusion. This time also was chosen because lactic acid that is thought to contribute to ischemic cell changes in PGI is at a maximum after 30 min of reperfusion.

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