scholarly journals Ethanol affects NMDA receptor signaling at climbing fiber-Purkinje cell synapses in mice and impairs cerebellar LTD

2013 ◽  
Vol 109 (5) ◽  
pp. 1333-1342 ◽  
Author(s):  
Qionger He ◽  
Heather Titley ◽  
Giorgio Grasselli ◽  
Claire Piochon ◽  
Christian Hansel
Keyword(s):  
Nmda Receptor ◽  
Purkinje Cell ◽  
Nmda Receptors ◽  
Purkinje Cells ◽  
Climbing Fiber ◽  
Receptor Signaling ◽  
Whole Cell Patch Clamp ◽  
Bath Application ◽  
Cerebellar Purkinje Cells ◽  
Circuit Function

Ethanol profoundly influences cerebellar circuit function and motor control. It has recently been demonstrated that functional N-methyl-d-aspartate (NMDA) receptors are postsynaptically expressed at climbing fiber (CF) to Purkinje cell synapses in the adult cerebellum. Using whole cell patch-clamp recordings from mouse cerebellar slices, we examined whether ethanol can affect NMDA receptor signaling in mature Purkinje cells. NMDA receptor-mediated currents were isolated by bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzol[f]quinoxaline (NBQX). The remaining d-2-amino-5-phosphonovaleric acid (d-APV)-sensitive current was reduced by ethanol at concentrations as low as 10 mM. At a concentration of 50 mM ethanol, the blockade of d-APV-sensitive CF-excitatory postsynaptic currents was significantly stronger. Ethanol also altered the waveform of CF-evoked complex spikes by reducing the afterdepolarization. This effect was not seen when NMDA receptors were blocked by d-APV before ethanol wash-in. In contrast to CF synaptic transmission, parallel fiber (PF) synaptic inputs were not affected by ethanol. Finally, ethanol (10 mM) impaired long-term depression (LTD) at PF to Purkinje cell synapses as induced under control conditions by paired PF and CF activity. However, LTD induced by pairing PF stimulation with depolarizing voltage steps (substituting for CF activation) was not blocked by ethanol. These observations suggest that the sensitivity of cerebellar circuit function and plasticity to low concentrations of ethanol may be caused by an ethanol-mediated impairment of NMDA receptor signaling at CF synapses onto cerebellar Purkinje cells.

Topography and Reciprocal Activity of Cerebellar Purkinje Cells in the Uvula-Nodulus Modulated by Vestibular Stimulation

1997 ◽  
Vol 78 (6) ◽  
pp. 3083-3094 ◽  
Author(s):  
H. Fushiki ◽  
N. H. Barmack
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Semicircular Canals ◽  
Vertical Axis ◽  
Longitudinal Axis ◽  
Vestibular Stimulation ◽  
Climbing Fiber ◽  
Null Plane ◽  
Cerebellar Purkinje Cells ◽  
Vertical Semicircular Canals

Fushiki, H. and N. H. Barmack. Topography and reciprocal activity of cerebellar Purkinje cells in the uvula-nodulus modulated by vestibular stimulation. J. Neurophysiol. 78: 3083–3094, 1997. In the rabbit uvula-nodulus, vestibular and optokinetic information is mapped onto parasagittal zones by climbing fibers. These zones are related functionally to different pairs of vertical semicircular canals, otolithic inputs and horizontal optokinetic inputs. Vestibular stimulation restricted to one of these zones modulates climbing fiber responses (CFRs). Within each of these zones, simple spikes (SSs) are modulated reciprocally with CFRs. In rabbits anesthetized with chloralose-urethan, we have used vestibular and optokinetic stimulation to evoke CFRs within a parasagittal zone while recording from Purkinje cells in adjacent zones. We have examined whether the CFRs evoked by vestibular stimulation in one zone influence the SSs of an adjacent zone. CFRs and SSs were recorded during roll vestibular stimulation. The orientation of the head of the rabbit with respect to the axis of rotation was varied systematically so that a climbing fiber null plane could be determined. This null plane was the orientation of the head about the vertical axis at which no modulation of the CFR was observed during rotation about the longitudinal axis of the vestibular rate table. In the left uvula-nodulus, a medial sagittal strip extending through all the folia contained Purkinje cells with CFRs that had optimal planes of stimulation coplanar with the left posterior-right anterior semicircular canals (LPC-RAC). Lateral to this strip was a strip of Purkinje cells with CFRs that were characterized by optimal planes corresponding to stimulation of the left anterior-right posterior semicircular canals (LAC-RPC). SSs in Purkinje cells were modulated out of phase with CFRs from the same Purkinje cell. The depth of modulation of both CFRs and SSs was reduced during rotation in the climbing fiber “null plane”. The depth of modulation of SSs was greatest when recorded from Purkinje cells located at the center of semicircular canal-related strip. We observed that 1) all folia of the uvula-nodulus receive vestibular climbing fiber inputs; 2) these climbing fiber inputs convey information from the vertical semicircular canals and otoliths but not the horizontal semicircular canals; 3) CFRs evoked in a particular sagittal zone do not influence SSs in adjacent zones; 4) modulation of a CFRs in a particular Purkinje cell can occur without modulation of SSs in the same Purkinje cell, although modulation of SSs was not observed in the absence of CFR modulation; and 5) modulation of SSs sometimes preceded that of CFRs in the same cell, implying that interneuronal pathways may contribute to SS modulation. Climbing fiber-driven Golgi cells, the inhibitory axon terminals of which end on granule cell dendrites in the classic glomerular synapse, may provide this interneuronal mechanism.

Glycine regulation of synaptic NMDA receptors in hippocampal neurons

1996 ◽  
Vol 76 (5) ◽  
pp. 3415-3424 ◽  
Author(s):  
K. S. Wilcox ◽  
R. M. Fitzsimonds ◽  
B. Johnson ◽  
M. A. Dichter
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
Time Course ◽  
Hippocampal Slices ◽  
Maximal Effect ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Dissociated Cell Culture ◽  
Cultured Hippocampal Neurons

1. Although glycine has been identified as a required coagonist with glutamate at N-methyl-D-aspartate (NMDA) receptors, the understanding of glycine's role in excitatory synaptic neurotransmission is quite limited. In the present study, we used the whole cell patch-clamp technique to examine the ability of glycine to regulate current flow through synaptic NMDA receptors at excitatory synapses between cultured hippocampal neurons and in acutely isolated hippocampal slices. 2. These studies demonstrate that the glycine modulatory site on the synaptic NMDA receptor is not saturated under baseline conditions and that increased glycine concentrations can markedly increased NMDA-receptor-mediated excitatory postsynaptic currents (EPSCs) in hippocampal neurons in both dissociated cell culture and in slice. Saturation of the maximal effect of glycine takes place at different concentrations for different cells in culture, suggesting the presence of heterogenous NMDA receptor subunit compositions. 3. Bath-applied glycine had no effect on the time course of EPSCs in either brain slice or culture, indicating that desensitization of the NMDA receptor is not prevented by glycine over the time course of an EPSC. 4. When extracellular glycine concentration is high, all miniature EPSCs recorded in the cultured hippocampal neurons contained NMDA components, indicating that segregation of non-NMDA receptors at individual synaptic boutons does not occur.

Normal adult climbing fiber monoinnervation of cerebellar Purkinje cells in mice lacking MHC class I molecules

2008 ◽  
Vol 68 (8) ◽  
pp. 997-1006 ◽  
Author(s):  
Mathieu Letellier ◽  
Melina L. Willson ◽  
Vanessa Gautheron ◽  
Jean Mariani ◽  
Ann M. Lohof
Keyword(s):  
Purkinje Cells ◽  
Mhc Class I ◽  
Climbing Fiber ◽  
Class I ◽  
Normal Adult ◽  
Cerebellar Purkinje Cells ◽  
Mhc Class I Molecules

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

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.

scholarly journals Activation of MAP3K DLK and LZK in Purkinje Cells Causes Rapid and Slow Degeneration Depending on Signaling Strength

2020 ◽  
Author(s):  
Yunbo Li ◽  
Erin M Ritchie ◽  
Christopher L. Steinke ◽  
Cai Qi ◽  
Lizhen Chen ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Leucine Zipper ◽  
Activity Levels ◽  
Cell Type ◽  
Cell Degeneration ◽  
Mechanistic Basis ◽  
Cerebellar Purkinje Cells ◽  
Jnk Activation

SummaryThe conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Mkk7, strongly attenuates Purkinje cell degeneration induced by activation of LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

scholarly journals Predictive and reactive reward signals conveyed by climbing fiber inputs to cerebellar Purkinje cells

2019 ◽  
Vol 22 (6) ◽  
pp. 950-962 ◽  
Author(s):  
Dimitar Kostadinov ◽  
Maxime Beau ◽  
Marta Blanco-Pozo ◽  
Michael Häusser
Keyword(s):  
Purkinje Cells ◽  
Climbing Fiber ◽  
Cerebellar Purkinje Cells

scholarly journals Expression of the yes proto-oncogene in cerebellar Purkinje cells.

1989 ◽  
Vol 9 (10) ◽  
pp. 4545-4549 ◽  
Author(s):  
M Sudol ◽  
C F Kuo ◽  
L Shigemitsu ◽  
A Alvarez-Buylla
Keyword(s):  
In Situ Hybridization ◽  
Purkinje Cell ◽  
Gene Product ◽  
Purkinje Cells ◽  
Immunofluorescent Staining ◽  
Cell Degeneration ◽  
Functional Studies ◽  
Cerebellar Purkinje Cells ◽  
The Brain

To identify the kinds of cells in the brain that express the yes proto-oncogene, we examined chicken brains by using immunofluorescent staining and in situ hybridization. Both approaches showed that the highest level of the yes gene product was in cerebellar Purkinje cells. In addition, we analyzed Purkinje cell degeneration (pcd) mutant mice. The level of yes mRNA in cerebella of pcd mutants was four times lower than that found in cerebella of normal littermates. Our studies point to Purkinje cells as an attractive model for functional studies of the yes protein.

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