scholarly journals Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination in Kcnc3 Mutants

2008 ◽  
Vol 28 (18) ◽  
pp. 4640-4648 ◽  
Author(s):  
E. C. Hurlock ◽  
A. McMahon ◽  
R. H. Joho
Keyword(s):  
Purkinje Cell ◽  
Motor Coordination ◽  
Complex Spikes

scholarly journals P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

2008 ◽  
Vol 105 (11) ◽  
pp. 4483-4488 ◽  
Author(s):  
S. Donald ◽  
T. Humby ◽  
I. Fyfe ◽  
A. Segonds-Pichon ◽  
S. A. Walker ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Motor Coordination ◽  
Cell Dendrite ◽  
Dendrite Morphology ◽  
Purkinje Cell Dendrite

scholarly journals PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination

2015 ◽  
Vol 1 (11) ◽  
pp. e1500615 ◽  
Author(s):  
Jun-Dal Kim ◽  
Kyung-Eui Park ◽  
Junji Ishida ◽  
Koichiro Kako ◽  
Juri Hamada ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Purkinje Cell ◽  
Phospholipase D ◽  
Motor Coordination ◽  
Dendritic Arborization ◽  
Axonal Outgrowth ◽  
Arginine Methyltransferase ◽  
Dendritic Trees ◽  
Motor Behaviors ◽  
Abnormal Motor

The development of vertebrate neurons requires a change in membrane phosphatidylcholine (PC) metabolism. Although PC hydrolysis is essential for enhanced axonal outgrowth mediated by phospholipase D (PLD), less is known about the determinants of PC metabolism on dendritic arborization. We show that protein arginine methyltransferase 8 (PRMT8) acts as a phospholipase that directly hydrolyzes PC, generating choline and phosphatidic acid. We found that PRMT8 knockout mice (prmt8−/−) displayed abnormal motor behaviors, including hindlimb clasping and hyperactivity. Moreover, prmt8−/− mice and TALEN-induced zebrafish prmt8 mutants and morphants showed abnormal phenotypes, including the development of dendritic trees in Purkinje cells and altered cerebellar structure. Choline and acetylcholine levels were significantly decreased, whereas PC levels were increased, in the cerebellum of prmt8−/− mice. Our findings suggest that PRMT8 acts both as an arginine methyltransferase and as a PC-hydrolyzing PLD that is essential for proper neurological functions.

Impaired Motor Function in Mice With Cell-Specific Knockout of Sodium Channel Scn8a (NaV1.6) in Cerebellar Purkinje Neurons and Granule Cells

2006 ◽  
Vol 96 (2) ◽  
pp. 785-793 ◽  
Author(s):  
Stephen I. Levin ◽  
Zayd M. Khaliq ◽  
Teresa K. Aman ◽  
Tina M. Grieco ◽  
Jennifer A. Kearney ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Motor Coordination ◽  
Granule Cells ◽  
Motor Behavior ◽  
Physiological Role ◽  
Motor Dysfunction ◽  
Purkinje Neurons ◽  
Na Channel ◽  
Α Subunit ◽  
Firing Rates

The Scn8a gene encodes the voltage-gated Na channel α subunit NaV1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate Scn8a in all cells result in severe motor dysfunction and premature death, precluding analysis of the physiological role of NaV1.6 in different neuronal types. To test the effect of cerebellar NaV1.6 on motor coordination in mice, we used the Cre-lox system to eliminate Scn8a expression exclusively in Purkinje neurons (Purkinje KO) and/or granule neurons (granule KO). Whereas granule KO mice had only minor behavioral defects, adult Purkinje KO mice exhibited ataxia, tremor, and impaired coordination. These disorders were exacerbated in double mutants lacking Scn8a in both Purkinje and granule cells (double KO). In Purkinje cells isolated from adult Purkinje KO and double KO but not granule KO mice, the ratio of resurgent-to-transient tetrodotoxin- (TTX)-sensitive Na current amplitudes decreased from ∼15 to ∼5%. In cerebellar slices, Purkinje cell spontaneous and maximal firing rates were reduced 10-fold and twofold relative to control in Purkinje KO and double KO but not granule KO mice. Additionally, short-term plasticity of high-frequency parallel fiber EPSCs was altered relative to control in Purkinje KO and double KO but not granule KO mice. These data suggest that the specialized kinetics of Purkinje Na channels depend directly on Scn8a expression. The loss of these channels leads to a decrease in Purkinje cell firing rates as well as a modification of the synaptic properties of afferent parallel fibers, with the ultimate consequence of disrupting motor behavior.

Developmental Changes in Evoked Purkinje Cell Complex Spike Responses

2003 ◽  
Vol 90 (4) ◽  
pp. 2349-2357 ◽  
Author(s):  
Daniel A. Nicholson ◽  
John H. Freeman
Keyword(s):  
Motor Learning ◽  
Purkinje Cell ◽  
Inferior Olive ◽  
Cell Complex ◽  
Climbing Fibers ◽  
Somatosensory Stimulation ◽  
Complex Spike ◽  
Long Latency ◽  
Inhibitory Feedback ◽  
Complex Spikes

The development of synaptic interconnections between the cerebellum and inferior olive, the sole source of climbing fibers, could contribute to the ontogeny of certain forms of motor learning (e.g., eyeblink conditioning). Purkinje cell complex spikes are produced exclusively by climbing fibers and exhibit short- and long-latency activity in response to somatosensory stimulation. Previous studies have demonstrated that evoked short- and long-latency complex spikes generally occur on separate trials and that this response segregation is regulated by inhibitory feedback to the inferior olive. The present experiment tested the hypothesis that complex spikes evoked by periorbital stimulation are regulated by inhibitory feedback from the cerebellum and that this feedback develops between postnatal days (PND) 17 and 24. Recordings from individual Purkinje cell complex spikes in urethan-anesthetized rats indicated that the segregation of short- and long-latency evoked complex spike activity emerges between PND17 and PND24. In addition, infusion of picrotoxin, a GABAA-receptor antagonist, into the inferior olive abolished the response pattern segregation in PND24 rats, producing evoked complex spike response patterns similar to those characteristic of younger rats. These data support the view that cerebellar feedback to the inferior olive, which is exclusively inhibitory, undergoes substantial changes in the same developmental time window in which certain forms of motor learning emerge.

scholarly journals GABAB Receptors Augment TRPC3-Mediated Slow Excitatory Postsynaptic Current to Regulate Cerebellar Purkinje Neuron Response to Type-1 Metabotropic Glutamate Receptor Activation

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 90 ◽  
Author(s):  
Jinbin Tian ◽  
Michael Zhu
Keyword(s):  
Purkinje Cell ◽  
Glutamate Receptor ◽  
Knockout Mice ◽  
Motor Coordination ◽  
Metabotropic Glutamate Receptor ◽  
Purkinje Neuron ◽  
Purkinje Neurons ◽  
Excitatory Postsynaptic Current ◽  
Metabotropic Glutamate

During strong parallel fiber stimulation, glutamate released at parallel fiber-Purkinje cell synapses activates type-1 metabotropic glutamate receptor (mGluR1) to trigger a slow excitatory postsynaptic current (sEPSC) in cerebellar Purkinje neurons. The sEPSC is mediated by transient receptor potential canonical 3 (TRPC3) channels. Often co-localized with mGluR1 in Purkinje neuron dendrites are type B γ-aminobutyric acid receptors (GABABRs) that respond to inhibitory synaptic inputs from interneurons located in the molecular layer of cerebellar cortex. It has been shown that activation of postsynaptic GABABRs potentiates mGluR1 activation-evoked sEPSC in Purkinje cells, but the underlying molecular mechanism remains elusive. Here we report that the augmentation of mGluR1-sEPSC by GABABR activation in Purkinje neurons is completely absent in TRPC3 knockout mice, but totally intact in TRPC1-, TRPC4-, and TRPC1,4,5,6-knockout mice, suggesting that TRPC3 is the only TRPC isoform that mediates the potentiation. Moreover, our results indicate that the potentiation reflects a postsynaptic mechanism that requires both GABABRs and mGluR1 because it is unaffected by blocking neurotransmission with tetrodotoxin but blocked by inhibiting either GABABRs or mGluR1. Furthermore, we show that the co-stimulation of GABABRs has an effect on shaping the response of Purkinje cell firing to mGluR1-sEPSC, revealing a new function of inhibitory input on excitatory neurotransmission. We conclude that postsynaptic GABABRs regulate Purkinje cell responses to strong glutamatergic stimulation through modulation of mGluR1-TRPC3 coupling. Since mGluR1-TRPC3 coupling is essential in cerebellar long-term depression, synapse elimination, and motor coordination, our findings may have implications in essential cerebellar functions, such as motor coordination and learning.

scholarly journals The dynamic relationship between cerebellar Purkinje cell simple spikes and the spikelet number of complex spikes

2016 ◽  
Vol 595 (1) ◽  
pp. 283-299 ◽  
Author(s):  
Amelia Burroughs ◽  
Andrew K. Wise ◽  
Jianqiang Xiao ◽  
Conor Houghton ◽  
Tianyu Tang ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Cerebellar Purkinje Cell ◽  
Spikelet Number ◽  
Dynamic Relationship ◽  
Complex Spikes

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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