Role of the vesicular transporter VGLUT3 in retrograde release of glutamate by cerebellar Purkinje cells

In the cerebellum, retrograde release of glutamate (Glu) by Purkinje cells (PCs) participates in the control of presynaptic neurotransmitter release responsible for the late component of depolarization-induced suppression of excitation (DSE), as well as for depolarization-induced potentiation of inhibition (DPI). It might also participate in the depolarization-induced slow current (DISC) in PCs, although this contribution was later challenged. We also know that both DPI and DISC are soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent processes, although the molecular nature of the vesicular transporter was not determined. In PCs, VGLUT3 is the only known vesicular glutamate transporter identified and is expressed during the same developmental frame as when DPI, DISC, and the Glu-dependent component of DSE are observed. We therefore tested the hypothesis that all these processes depend on the presence of VGLUT3 by comparing the Glu-dependent component of DSE, DPI, and DISC in nearly mature (2- to 3-wk-old) wild-type and VGLUT3 knockout mice. Our data demonstrate that, in nearly mature mice, the slow component of DSE occurs through vesicular release of Glu that involves VGLUT3. This Glu-dependent component of DSE is no longer present in fully mature mice. This study also establishes that, in nearly mature mice, DPI also depends on the presence of VGLUT3, whereas this is not the case for DISC. Finally, the unusually large basal paired-pulse facilitation observed in nearly mature VGLUT3−/− mice but not in adult ones suggests that some basal retrograde release of Glu occurs during development and contributes to basal concentrations of extracellular Glu.

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Mice With Monoallelic GNAO1 Loss Exhibit Reduced Inhibitory Synaptic Input To Cerebellar Purkinje Cells

10.1101/2021.09.23.461583 ◽

2021 ◽

Author(s):

Huijie Feng ◽

Yukun Yuan ◽

Michael R Williams ◽

Alex Roy ◽

Jeffrey Leipprandt ◽

...

Keyword(s):

Synaptic Transmission ◽

Purkinje Cells ◽

Gabab Receptor ◽

Molecular Layer ◽

Loss Of Function ◽

Whole Cell Patch Clamp ◽

The Difference ◽

G Protein Alpha Subunit ◽

Cerebellar Purkinje Cells

GNAO1 encodes Gαo, a heterotrimeric G protein alpha subunit in the Gi/o family. In this report, we used a Gnao1 mouse model G203R previously described as a gain-of-function Gnao1 mutant with movement abnormalities and enhanced seizure susceptibility. Here, we report an unexpected second mutation resulting in a loss-of-function Gαo protein and describe alterations in central synaptic transmission. Whole cell patch clamp recordings from Purkinje cells (PCs) in acute cerebellar slices from Gnao1 mutant mice showed significantly lower frequencies of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) compared to WT mice. There was no significant change in sEPSCs or mEPSCs. Whereas mIPSC frequency was reduced, mIPSC amplitudes were not affected, suggesting a presynaptic mechanism of action. A modest decrease in the number of molecular layer interneurons was insufficient to explain the magnitude of IPSC suppression. Paradoxically, Gi/o inhibitors (pertussis toxin), enhanced the mutant-suppressed mIPSC frequency and eliminated the difference between WT and Gnao1 mice. While GABAB receptor regulates mIPSCs, neither agonists nor antagonists of this receptor altered function in the mutant mouse PCs. This study is the first electrophysiological investigation of the role of Gi/o protein in cerebellar synaptic transmission using an animal model with a loss-of-function Gi/o protein.

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Modulatory role of serotonin on GABA-elicited inhibition of cerebellar Purkinje cells

Neuroscience ◽

10.1016/0306-4522(89)90358-8 ◽

1989 ◽

Vol 30 (1) ◽

pp. 117-125 ◽

Cited By ~ 25

Author(s):

J.C. Strahlendorf ◽

M. Lee ◽

H.K. Strahlendorf

Keyword(s):

Purkinje Cells ◽

Cerebellar Purkinje Cells

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Functional Role of Cerebellar Purkinje Cells in Ontogenesis of Postural-Motor Reactions in Mature- and Immature-Born Mammals

Journal of Evolutionary Biochemistry and Physiology ◽

10.1023/b:joey.0000023489.71026.0b ◽

2003 ◽

Vol 39 (6) ◽

pp. 691-701 ◽

Cited By ~ 1

Author(s):

R. A. Grigorian ◽

E. I. Prigarina ◽

T. L. Oleinik ◽

T. V. Karelina

Keyword(s):

Purkinje Cells ◽

Functional Role ◽

Cerebellar Purkinje Cells

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Commentary: Critical role of JSAP1 and JLP in axonal transport in the cerebellar Purkinje cells of mice

Journal of Neurology and Neuromedicine ◽

10.29245/2572.942x/2016/8.1095 ◽

2016 ◽

Vol 1 (8) ◽

pp. 19-21

Author(s):

Katsuji Yoshioka

Keyword(s):

Axonal Transport ◽

Purkinje Cells ◽

Critical Role ◽

Cerebellar Purkinje Cells

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Spike burst–pause dynamics of Purkinje cells regulate sensorimotor adaptation

10.1101/347252 ◽

2018 ◽

Author(s):

Niceto R. Luque ◽

Francisco Naveros ◽

Richard R. Carrillo ◽

Eduardo Ros ◽

Angelo Arleo

Keyword(s):

Purkinje Cell ◽

Purkinje Cells ◽

Vestibular Nuclei ◽

Response Patterns ◽

Spike Burst ◽

Vor Adaptation ◽

Cell Firing ◽

Cerebellar Purkinje Cells ◽

Oculomotor Adaptation

AbstractCerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of targeted medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.Author SummaryCerebellar Purkinje cells regulate accurate eye movement coordination. However, it remains unclear how cerebellar-dependent oculomotor adaptation depends on the interplay between Purkinje cell characteristic response patterns: tonic, high-frequency bursting, and post-complex spike pauses. We explore the role of Purkinje spike burst-pause dynamics in VOR adaptation. A biophysical model of Purkinje cell is at the core of a spiking network model, which captures the cerebellar microcircuit properties and incorporates spike-based synaptic plasticity mechanisms at different cerebellar sites. We show that Purkinje spike burst-pause dynamics are critical for (1) gating the vestibular-motor response association during VOR acquisition; (2) mediating the LTD/LTP balance for VOR consolidation; (3) reshaping synaptic efficacy distributions for VOR phase-reversal adaptation; (4) explaining the reversal VOR gain discontinuities during sleeping.

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Modulation of Increased mGluR1 Signaling by RGS8 Protects Purkinje Cells From Dendritic Reduction and Could Be a Common Mechanism in Diverse Forms of Spinocerebellar Ataxia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.569889 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Qin-Wei Wu ◽

Josef P. Kapfhammer

Keyword(s):

Purkinje Cells ◽

Spinocerebellar Ataxia ◽

Common Mechanism ◽

G Protein Signaling ◽

Protein Signaling ◽

Spinocerebellar Ataxias ◽

Negative Effects ◽

The Moment ◽

Cerebellar Purkinje Cells

Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases which are caused by diverse genetic mutations in a variety of different genes. We have identified RGS8, a regulator of G-protein signaling, as one of the genes which are dysregulated in different mouse models of SCA (e.g., SCA1, SCA2, SCA7, and SCA14). In the moment, little is known about the role of RGS8 for pathogenesis of spinocerebellar ataxia. We have studied the expression of RGS8 in the cerebellum in more detail and show that it is specifically expressed in mouse cerebellar Purkinje cells. In a mouse model of SCA14 with increased PKCγ activity, RGS8 expression was also increased. RGS8 overexpression could partially counteract the negative effects of DHPG-induced mGluR1 signaling for the expansion of Purkinje cell dendrites. Our results suggest that the increased expression of RGS8 is an important mediator of mGluR1 pathway dysregulation in Purkinje cells. These findings provide new insights in the role of RGS8 and mGluR1 signaling in Purkinje cells and for the pathology of SCAs.

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Altered Glutamate Receptor Ionotropic Delta Subunit 2 Expression in Stau2-Deficient Cerebellar Purkinje Cells in the Adult Brain

International Journal of Molecular Sciences ◽

10.3390/ijms20071797 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1797 ◽

Cited By ~ 1

Author(s):

Helena F. Pernice ◽

Rico Schieweck ◽

Mehrnoosh Jafari ◽

Tobias Straub ◽

Martin Bilban ◽

...

Keyword(s):

Purkinje Cells ◽

Glutamate Receptor ◽

Rna Binding ◽

Wheel Running ◽

Adult Brain ◽

Learning Abilities ◽

Cerebellar Purkinje Cells ◽

And Function ◽

Delta Subunit

Staufen2 (Stau2) is an RNA-binding protein that is involved in dendritic spine morphogenesis and function. Several studies have recently investigated the role of Stau2 in the regulation of its neuronal target mRNAs, with particular focus on the hippocampus. Here, we provide evidence for Stau2 expression and function in cerebellar Purkinje cells. We show that Stau2 downregulation (Stau2GT) led to an increase of glutamate receptor ionotropic delta subunit 2 (GluD2) in Purkinje cells when animals performed physical activity by voluntary wheel running compared with the age-matched wildtype (WT) mice (C57Bl/6J). Furthermore, Stau2GT mice showed lower performance in motor coordination assays but enhanced motor learning abilities than did WT mice, concomitantly with an increase in dendritic GluD2 expression. Together, our results suggest the novel role of Stau2 in Purkinje cell synaptogenesis in the mouse cerebellum.

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