Purkinje Cell NMDA Receptors Assume a Key Role in Synaptic Gain Control in the Mature Cerebellum

Piochon, Claire; Lévénès, Carole; Ohtsuki, Gen; Hansel, Christian

doi:10.1523/jneurosci.4344-10.2010

Cited by 92 publications

(122 citation statements)

References 32 publications

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“…1) leads to the question of whether CF activity indeed promotes LTD by amplifying calcium transients, or whether it contributes other signaling factors that trigger the switch toward LTD. For example, CF activity results in the release of corticotropin-releasing factor, which promotes LTD at PF and CF synapses by activation of PKC (33,34). In addition, in the mature cerebellum, CF stimulation recruits a specific calcium source that is not available at PF synapses, postsynaptically located NMDA receptors (7,35,36). It is conceivable that these CF-specific signaling components contribute to LTD.…”

Section: Discussionmentioning

confidence: 99%

“…This activation pattern is applied at 1 Hz for 5 min. With this protocol, too, omission of CF activation causes LTP instead (7). All stimulus protocols cause postsynaptically expressed forms of LTD/LTP (6,7).…”

Section: Significancementioning

confidence: 92%

“…With this protocol, too, omission of CF activation causes LTP instead (7). All stimulus protocols cause postsynaptically expressed forms of LTD/LTP (6,7). In the following, we will use the terms "low-frequency protocol" and "high-frequency protocol" to refer to the highest lead frequency within the PF stimulus patterns.…”

Section: Significancementioning

confidence: 99%

“…However, LTP and LTD can also be induced at the same stimulus frequency. This phenomenon has been demonstrated at hippocampal, neocortical, and cerebellar synapses, where potentiation and depression mechanisms operate over a wide range of activation frequencies (2)(3)(4)(5)(6)(7). In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2,5).…”

mentioning

confidence: 95%

“…At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, and at both frequencies, climbing fiber (CF) coactivation promotes LTD, whereas LTP results from PF stimulation alone (6,7,15,16). CF coactivity leads to supralinear spine calcium signaling (17), which helps to reach the calcium threshold for LTD, which is higher than the threshold for LTP at these synapses (6).…”

mentioning

confidence: 99%

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Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Piochon

Titley

Simmons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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At glutamatergic synapses, both long-term potentiation (LTP) and long-term depression (LTD) can be induced at the same synaptic activation frequency. Instructive signals determine whether LTP or LTD is induced, by modulating local calcium transients. Synapses maintain the ability to potentiate or depress over a wide frequency range, but it remains unknown how calcium-controlled plasticity operates when frequency variations alone cause differences in calcium amplitudes. We addressed this problem at cerebellar parallel fiber-Purkinje cell synapses, which can undergo LTD or LTP in response to 1-Hz and 100-Hz stimulation. We observed that high-frequency activation elicits larger spine calcium transients than low-frequency stimulation under all stimulus conditions, but, regardless of activation frequency, climbing fiber (CF) coactivation provides an instructive signal that further enhances calcium transients and promotes LTD. At both frequencies, buffering calcium prevents LTD induction and LTP results instead, identifying the enhanced calcium signal amplitude as the critical parameter contributed by the instructive CF signal. These observations show that it is not absolute calcium amplitudes that determine whether LTD or LTP is evoked but, instead, the LTD threshold slides, thus preserving the requirement for relatively larger calcium transients for LTD than for LTP induction at any given stimulus frequency. Cerebellar LTD depends on the activation of calcium/ calmodulin-dependent kinase II (CaMKII). Using genetically modified (TT305/6VA and T305D) mice, we identified α-CaMKII inhibition upon autophosphorylation at Thr305/306 as a molecular event underlying the threshold shift. This mechanism enables frequencyindependent plasticity control by the instructive CF signal based on relative, not absolute, calcium thresholds.S ynaptic activation frequency is an important factor in the induction of long-term potentiation (LTP) and long-term depression (LTD). For example, it has been shown at Schaffer collateral-CA1 pyramidal cell synapses that application of 900 pulses at 1-3 Hz causes LTD, whereas the same number of pulses applied at 50 Hz causes LTP (1). However, LTP and LTD can also be induced at the same stimulus frequency. This phenomenon has been demonstrated at hippocampal, neocortical, and cerebellar synapses, where potentiation and depression mechanisms operate over a wide range of activation frequencies (2-7). In the neocortex and hippocampus, the level of postsynaptic depolarization determines whether LTP or LTD results from stimulation at a given frequency (2, 5). These voltage-dependent thresholds for LTP and LTD induction reflect thresholds in calcium signal amplitudes (3,4,(8)(9)(10)(11)) that, when maintained for sufficiently long time periods (12), control synaptic plasticity in concert with distinct calcium sensors that are restricted to local microenvironments (13,14).At cerebellar parallel fiber (PF)-Purkinje cell synapses, both LTP and LTD can be induced using 1-Hz and 100-Hz PF stimulation protocols, ...

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 92%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

See 3 more Smart Citations

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Piochon

Titley

Simmons

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Plasticity mechanisms of genetically distinct Purkinje cells

Voerman,

Broersen,

Swagemakers

et al. 2024

BioEssays

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Despite its uniform appearance, the cerebellar cortex is highly heterogeneous in terms of structure, genetics and physiology. Purkinje cells (PCs), the principal and sole output neurons of the cerebellar cortex, can be categorized into multiple populations that differentially express molecular markers and display distinctive physiological features. Such features include action potential rate, but also their propensity for synaptic and intrinsic plasticity. However, the precise molecular and genetic factors that correlate with the differential physiological properties of PCs remain elusive. In this article, we provide a detailed overview of the cellular mechanisms that regulate PC activity and plasticity. We further perform a pathway analysis to highlight how molecular characteristics of specific PC populations may influence their physiology and plasticity mechanisms.

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Long Term Depression in the Granule Cell-Purkinje Cell Synapse

Tanaka-Yamamoto

2022

Encyclopedia of Computational Neuroscience

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Purkinje Cell NMDA Receptors Assume a Key Role in Synaptic Gain Control in the Mature Cerebellum

Cited by 92 publications

References 32 publications

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Calcium threshold shift enables frequency-independent control of plasticity by an instructive signal

Plasticity mechanisms of genetically distinct Purkinje cells

Long Term Depression in the Granule Cell-Purkinje Cell Synapse

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