scholarly journals Climbing Fiber Discharge Regulates Cerebellar Functions by Controlling the Intrinsic Characteristics of Purkinje Cell Output

2007 ◽  
Vol 97 (4) ◽  
pp. 2590-2604 ◽  
Author(s):  
Bruce E. McKay ◽  
Jordan D. T. Engbers ◽  
W. Hamish Mehaffey ◽  
Grant R. J. Gordon ◽  
Michael L. Molineux ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Motor Coordination ◽  
Climbing Fiber ◽  
State Transitions ◽  
Cellular Functions ◽  
Complex Spike ◽  
Network Activation ◽  
Cellular Factors

The contribution of Purkinje cells to cerebellar motor coordination and learning is determined in part by the chronic and acute effects of climbing fiber (CF) afferents. Whereas the chronic effects of CF discharge, such as the depression of conjunctive parallel fiber (PF) inputs, are well established, the acute cellular functions of CF discharge remain incompletely understood. In rat cerebellar slices, we show that CF discharge presented at physiological frequencies substantially modifies the frequency and pattern of Purkinje cell spike output in vitro. Repetitive CF discharge converts a spontaneous trimodal pattern of output characteristic of Purkinje cells in vitro to a more naturalistic nonbursting pattern consisting of spike trains interrupted by short CF-evoked pauses or longer pauses associated with state transitions. All effects of CF discharge could be reproduced in the presence of synaptic blockers by using current injections to simulate complex spike depolarizations, revealing that CF-evoked changes in Purkinje cell output can occur independently of network activation. Rather postsynaptic changes are sufficient to account for the CF-evoked block of trimodal activity and include at least the activation of Ca2+-dependent K+ channels. Furthermore by controlling the frequency of Purkinje cell spike output over three discrete firing levels, CF discharge modulates the gain of Purkinje cell responsiveness to PF inputs in vitro through postsynaptic mechanisms triggered by the complex spike depolarization. The ability for CF discharge to acutely modulate diverse aspects of Purkinje cell output provides important insights into the probable cellular factors contributing to motor disturbances following CF denervation.

Increase in Purkinje cell gain associated with naturally activated climbing fiber input

1983 ◽  
Vol 50 (1) ◽  
pp. 205-219 ◽  
Author(s):  
T. J. Ebner ◽  
Q. X. Yu ◽  
J. R. Bloedel
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Mossy Fiber ◽  
Climbing Fiber ◽  
Peripheral Stimulus ◽  
Short Term ◽  
Spike Response ◽  
Complex Spike ◽  
Simple Spike ◽  
Complex Spikes

These experiments were designed to test the hypothesis that climbing fiber inputs evoked by a peripheral stimulus increase the responsiveness of Purkinje cells to mossy fiber inputs. This hypothesis was based on a previous series of observations demonstrating that spontaneous climbing fiber inputs are associated with an accentuation of the Purkinje cell responses to subsequent mossy fiber inputs (10, 12). Furthermore, short-term nonpersistent interactions between climbing and mossy fiber inputs have been an important aspect of many theories of cerebellar function (5, 7, 8, 12, 36). Extracellular unitary recordings were made from Purkinje cells in lobule V of decerebrate, unanesthetized cats. To activate mossy and climbing fiber inputs, the forepaw was passively flexed by a Ling vibrator system. A data analysis was developed to sort the simple spike trials into two groups, based on the presence or absence of complex spikes activated by the stimulus. In addition, during those trials in which complex spikes were activated, the simple spike train was aligned on the occurrence of the complex spike. For each simple spike response to the forepaw input, the average firing rate during the response was compared to background both in those trials in which complex spikes were activated and in those in which they were not. The ratio of the response amplitudes in the histograms constructed from these two groups of trials permitted a quantification of the change in responsiveness when climbing fiber inputs were activated. The results show that both excitatory and inhibitory simple spike responses are accentuated when associated with the activation of a complex spike. Using an arbitrary level of a gain change ratio of 120% as indicating a significant modification, 64% of the response components analyzed increased their amplitude when climbing fiber input was present. Simple spike response components occurring prior to complex spike activation were usually not accentuated, although in a few cells the amplitude of this component of the response increased. In addition, in a small number of cells the occurrence of complex spikes was associated with a new simple spike component. For excitatory responses, the magnitude of the gain change ratio was shown to be inversely related to the amplitude of the simple spike response evoked by the mossy fiber inputs. The data obtained is consistent with the hypothesis that the climbing fiber input is associated with an increase in the responsiveness of Purkinje cells to mossy fiber inputs. The increased responsiveness occurs whether the simple spike modulation evoked by the peripheral stimulus is excitatory or inhibitory. The change in responsiveness is short term and nonpersistent. It is argued that the activation of climbing fiber inputs to the cerebellar cortex is associated with an increase in the gain of Purkinje cells to mossy fiber inputs activated by natural peripheral stimuli.

An active membrane model of the cerebellar Purkinje cell II. Simulation of synaptic responses

1994 ◽  
Vol 71 (1) ◽  
pp. 401-419 ◽  
Author(s):  
E. De Schutter ◽  
J. M. Bower
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Average Frequency ◽  
Climbing Fiber ◽  
Cerebellar Purkinje Cell ◽  
Inhibitory Synapses ◽  
Complex Spike ◽  
Simple Spike ◽  
Spike Firing

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. All model parameters remained as described previously, leaving maximum synaptic conductance as the only parameter that was tuned in the studies described in this paper. Under these conditions the model was capable of reproducing physiological recorded responses to each of the major types of synaptic input. 2. When excitatory synapses were activated on the smooth dendrites of the model, the model generated a complex dendritic Ca2+ spike similar to that generated by climbing fiber inputs. Examination of the model showed that activation of P-type Ca2+ channels in both the smooth and spiny dendrites augmented the depolarization during the complex spike and that Ca(2+)-activated K+ channels in the same dendritic regions determined the duration of the spike. When these synapses were activated under simulated current-clamp conditions the model also generated the characteristic dual reversal potential of the complex spike. The shape of the dendritic complex spike could be altered by changing the maximum conductance of the climbing fiber synapse and thus the amount of Ca2+ entering the cell. 3. To explore the background simple spike firing properties of Purkinje cells in vivo we added excitatory “parallel fiber” synapses to the spiny dendritic branches of the model. Continuous asynchronous activation of these granule cell synapses resulted in the generation of spontaneous sodium spikes. However, very low asynchronous input frequencies produced a highly regular, very fast rhythm (80–120 Hz), whereas slightly higher input frequencies resulted in Purkinje cell bursting. Both types of activity are uncharacteristic of in vivo Purkinje cell recordings. 4. Inhibitory synapses of the sort presumably generated by stellate cells were also added to the dendritic tree. When asynchronous activation of these inhibitory synapses was combined with continuous asynchronous excitatory input the model generated somatic action potentials in a much more stochastic pattern typical of real Purkinje cells. Under these conditions simulated inter-spike interval distributions resembled those found in experimental recordings. Also, as with in vivo recordings, the model did not generate dendritic bursts. This was mainly due to inhibition that suppressed the generation of dendritic Ca2+ spikes. 5. In the presence of asynchronous inhibition, changes in the average frequency of excitatory inputs modulated background simple spike firing frequencies in the natural range of Purkinje cell firing frequencies (30–100 Hz). This modulation was very sensitive to small changes in the average frequency of excitatory inputs.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Antoine M Valera ◽  
Francesca Binda ◽  
Sophie A Pawlowski ◽  
Jean-Luc Dupont ◽  
Jean-François Casella ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Granule Cell ◽  
Motor Coordination ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Synaptic Organization ◽  
Cerebellar Modules ◽  
Activity Dependent

Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex.

scholarly journals The rich get richer: synaptic remodeling between climbing fibers and Purkinje cells in the developing cerebellum begins with positive feedback addition of synapses

2019 ◽  
Author(s):  
Alyssa Michelle Wilson ◽  
Richard Schalek ◽  
Adi Suissa-Peleg ◽  
Thouis Ray Jones ◽  
Seymour Knowles-Barley ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Purkinje Cell ◽  
Postnatal Development ◽  
Purkinje Cells ◽  
Positive Feedback ◽  
Climbing Fiber ◽  
Climbing Fibers ◽  
List Type ◽  
Developing Cerebellum ◽  
Serial Electron Microscopy

SUMMARYDuring postnatal development, cerebellar climbing fibers strongly innervate a subset of their original Purkinje cell targets and eliminate their connections from the rest. In the adult, each climbing fiber innervates a small number of Purkinje cells and each Purkinje cell is innervated by a single climbing fiber. To get insight about the processes responsible for this remapping, we reconstructed serial electron microscopy datasets from mice during the first postnatal week. In contrast to adult connectivity, individual neonatal climbing fibers innervate many nearby Purkinje cells, and multiple climbing fibers innervate each Purkinje cell. Between postnatal days 3 and 7, Purkinje cells retract long dendrites and grow many proximal dendritic processes. On this changing landscape, individual climbing fibers selectively add many synapses to a subset of Purkinje cell targets in a positive-feedback manner, without pruning synapses from other Purkinje cells. The active zone sizes of synapses associated with powerful versus weak inputs are indistinguishable. These results show that changes in synapse number rather than synapse size are the predominant form of early developmental plasticity. Finally, although multiple climbing fibers innervate each Purkinje cell in early postnatal development, the number of climbing fibers and Purkinje cells in a local cerebellar region nearly match. Thus, initial over-innervation of Purkinje cells by climbing fibers is economical, in that the number of axons entering a region is enough to assure that each axon ends up with a postsynaptic target, and that none branched there in vain.HIGHLIGHTSDeveloping climbing fibers establish synapses on many neighboring Purkinje cells unlike the sparse pattern of innervation in later lifeClimbing fibers add many synapses onto a few of their Purkinje targets before the pruning stage in a rich-get-richer type processThe synapse sizes of strengthened and weakened climbing fiber inputs are indistinguishable.Exuberant branching of climbing fiber axons in early postnatal life appears to be economical because the numbers of axons and Purkinje cells in a local region match, ensuring that each axon can establish a long-lasting connection thereBLURBHigh-resolution serial electron microscopy reconstructions reveal that climbing fiber-Purkinje cell synaptic refinement in the developing cerebellum begins with significant synapse addition. Climbing fibers focus their synapses onto a smaller number of Purkinje cells by selectively adding synapses onto some target cells. All axons that project to a region in development play a role in the final connectivity.

scholarly journals Complex spike firing adapts to saliency of inputs and engages readiness to act

2020 ◽  
Author(s):  
Lorenzo Bina ◽  
Vincenzo Romano ◽  
Tycho M. Hoogland ◽  
Laurens W.J. Bosman ◽  
Chris I. De Zeeuw
Keyword(s):  
Purkinje Cell ◽  
Climbing Fiber ◽  
Sensory Stimulus ◽  
Motor Functions ◽  
Sensory Stimuli ◽  
Complex Spike ◽  
Trial Analysis ◽  
Salient Stimulus ◽  
Per Se ◽  
The Moment

AbstractThe cerebellum is involved in cognition next to motor coordination. During complex tasks, climbing fiber input to the cerebellum can deliver seemingly opposite signals, covering both motor and non-motor functions. To elucidate this ambiguity, we hypothesized that climbing fiber activity represents the saliency of inputs leading to action-readiness. We addressed this hypothesis by recording Purkinje cell activity in lateral cerebellum of awake mice learning go/no-go decisions based on entrained saliency of different sensory stimuli. As training progressed, the timing of climbing fiber signals switched in a coordinated fashion with that of Purkinje cell simple spikes towards the moment of occurrence of the salient stimulus that required action. Trial-by-trial analysis indicated that emerging climbing fiber activity is not linked to individual motor responses or rewards per se, but rather reflects the saliency of a particular sensory stimulus that engages a general readiness to act, bridging the non-motor with the motor functions.In briefMice were trained to identify the saliency of different sensory inputs in that they had to learn to ignore a prominent sound cue and respond to a light tactile cue in a Go/No-Go licking task. As the mice learned to discriminate the two inputs and respond to the proper signal, the Purkinje cells in the lateral cerebellum switched their climbing fiber activity (i.e., complex spike activity) towards the moment of occurrence of the salient stimulus that required a response, while concomitantly shifting the phase of their simple spike modulation. Trial-by-trial analysis indicates that the emerging climbing fiber activity is not linked to the occurrence of the motor response or reward per se, but rather reflects the saliency of a particular sensory stimulus engaging a general readiness to act.

Sodium Imaging of Climbing Fiber Innervation Fields in Developing Mouse Purkinje Cells

2003 ◽  
Vol 89 (5) ◽  
pp. 2555-2563 ◽  
Author(s):  
Bibiana Scelfo ◽  
Piergiorgio Strata ◽  
Thomas Knöpfel
Keyword(s):  
Nervous System ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Cell Body ◽  
Sodium Concentration ◽  
Climbing Fiber ◽  
Early Postnatal Development ◽  
Postsynaptic Currents ◽  
Sodium Imaging ◽  
Neuronal Connections

Maturation of specific neuronal connections in the mature nervous system includes elimination of redundant synapses formed earlier during development. In the cerebellum of adult animals, each Purkinje cell (PC) is innervated by a single climbing fiber (CF). In early postnatal development each PC is innervated by multiple CFs and elimination of synapses formed by supernumerary CFs occurs until monoinnervation is established at around postnatal day 20 (P20) in mice. It is not clear whether multiple CFs, or only a single CF, translocate from the cell body of immature PCs to the developing dendrite and, in case several CFs translocate, whether they share or segregate their innervation fields. To localize CF innervation fields, we imaged changes in postsynaptic sodium concentration resulting from CF-mediated postsynaptic currents. We found that more than one CF translocates from an innervation field on the cell body of the PC to the developing dendrite and that these CFs share rather than segregate their innervation fields. We concluded that both the soma and the proximal dendrite of the PC are territories of competition for the developing CFs and that the overlapping of their termination fields may be the prerequisite for a local process of elimination of all but one CF, as previously demonstrated in the developing neuromuscular junction.

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

1997 ◽  
Vol 94 (25) ◽  
pp. 14089-14094 ◽  
Author(s):  
S. Offermanns ◽  
K. Hashimoto ◽  
M. Watanabe ◽  
W. Sun ◽  
H. Kurihara ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Motor Coordination ◽  
Climbing Fiber ◽  
Cerebellar Purkinje Cells

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

2008 ◽  
Vol 100 (6) ◽  
pp. 3167-3174 ◽  
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.

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

2019 ◽  
Vol 21 (1) ◽  
pp. 216 ◽  
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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