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

AbstractHow do we learn to establish associations between arbitrary visual cues (like a red light) and movements (like braking the car)? We investigated the neural correlates of visuomotor association learning in the monkey mid-lateral cerebellum. Here we show that, during learning but not when the associations were overlearned, individual Purkinje cells reported the outcome of the monkey’s most recent decision, an error signal, which was independent of changes in hand movement or reaction time. At the population level, Purkinje cells collectively maintained a memory of the most recent decision throughout the entire trial period, updating it after every decision. This error signal decreased as the performance improved. Our results suggest a role of mid-lateral cerebellum in visuomotor associative learning and provide evidence that cerebellum could be a generalized learning system, essential in non-motor learning as well as motor learning.

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Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking G q

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.94.25.14089 ◽

1997 ◽

Vol 94 (25) ◽

pp. 14089-14094 ◽

Cited By ~ 171

Author(s):

S. Offermanns ◽

K. Hashimoto ◽

M. Watanabe ◽

W. Sun ◽

H. Kurihara ◽

...

Keyword(s):

Purkinje Cells ◽

Motor Coordination ◽

Climbing Fiber ◽

Cerebellar Purkinje Cells

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Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m111.253674 ◽

2011 ◽

Vol 286 (29) ◽

pp. 25848-25858 ◽

Cited By ~ 32

Author(s):

Davina V. Gutierrez ◽

Melanie D. Mark ◽

Olivia Masseck ◽

Takashi Maejima ◽

Denise Kuckelsberg ◽

...

Keyword(s):

Purkinje Cells ◽

Motor Coordination ◽

Cerebellar Purkinje Cells ◽

Optogenetic Control

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

Journal of Neuroscience ◽

10.1523/jneurosci.23-08-03469.2003 ◽

2003 ◽

Vol 23 (8) ◽

pp. 3469-3477 ◽

Cited By ~ 109

Author(s):

Jaroslaw J. Barski ◽

Jana Hartmann ◽

Christine R. Rose ◽

Freek Hoebeek ◽

Karin Mörl ◽

...

Keyword(s):

Purkinje Cells ◽

Motor Coordination ◽

Critical Determinant ◽

Cerebellar Purkinje Cells

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Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

Journal of Neurophysiology ◽

10.1152/jn.90384.2008 ◽

2008 ◽

Vol 100 (6) ◽

pp. 3167-3174 ◽

Cited By ~ 56

Author(s):

Amor Belmeguenai ◽

Paolo Botta ◽

John T. Weber ◽

Mario Carta ◽

Martijn De Ruiter ◽

...

Keyword(s):

Alcohol Consumption ◽

Motor Learning ◽

Synaptic Transmission ◽

Purkinje Cell ◽

Purkinje Cells ◽

Motor Coordination ◽

Parallel Fiber ◽

Calcium Currents ◽

Long Term Depression

Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption.

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Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

International Journal of Molecular Sciences ◽

10.3390/ijms21010216 ◽

2019 ◽

Vol 21 (1) ◽

pp. 216 ◽

Cited By ~ 3

Author(s):

Francesca Prestori ◽

Francesco Moccia ◽

Egidio D’Angelo

Keyword(s):

Animal Models ◽

Purkinje Cell ◽

Calcium Signaling ◽

Purkinje Cells ◽

Motor Coordination ◽

Cerebellar Atrophy ◽

Cerebellar Nuclei ◽

Spinocerebellar Ataxias ◽

Cell Degeneration ◽

Cerebellar Purkinje Cells

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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The Emerging Concept of Intrinsic Plasticity: Activity-dependent Modulation of Intrinsic Excitability in Cerebellar Purkinje Cells and Motor Learning

Experimental Neurobiology ◽

10.5607/en.2018.27.3.139 ◽

2018 ◽

Vol 27 (3) ◽

pp. 139-154 ◽

Cited By ~ 15

Author(s):

Hyun Geun Shim ◽

Yong-Seok Lee ◽

Sang Jeong Kim

Keyword(s):

Motor Learning ◽

Purkinje Cells ◽

Intrinsic Excitability ◽

Intrinsic Plasticity ◽

Cerebellar Purkinje Cells ◽

Activity Dependent

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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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