NMDA Receptor Contribution to the Climbing Fiber Response in the Adult Mouse Purkinje Cell

Piochon, Claire; Irinopoulou, Théano; Brusciano, Daniel; Bailly, Yannick; Mariani, Jean; Lévénès, Carole

doi:10.1523/jneurosci.2422-07.2007

Cited by 108 publications

(114 citation statements)

References 69 publications

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“…Although recent studies have shown that PCs of adult mice express functional NMDARs at synapses with climbing fibers (31,32), functional NMDARs are not present after postnatal day 7 in PCs of juvenile rats (33,34) (Fig. S2).…”

Section: Resultsmentioning

confidence: 92%

Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule

Bidoret¹,

Ayon²,

Barbour³

et al. 2009

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

136

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The detailed characterization of synaptic plasticity has led to the replacement of simple Hebbian rules by more complex rules depending on the order of presynaptic and postsynaptic action potentials. Here, we describe a mechanism endowing a plasticity rule with additional computational complexity-a dependence on the pattern of presynaptic action potentials. The classical Hebbian rule is based on detection of conjunctive presynaptic and postsynaptic activity by postsynaptic NMDA receptors, but there is also accumulating evidence for the existence of presynaptic NMDA receptors in several brain structures. Here, we examine the role of presynaptic NMDA receptors in defining the temporal structure of the plasticity rule governing induction of long-term depression (LTD) at the cerebellar parallel fiber-Purkinje cell synapse. We show that multiple presynaptic action potentials at frequencies between 40 Hz and 1 kHz are necessary for LTD induction. We characterize the subtype, kinetics, and role of presynaptic NMDA receptors involved in the induction of LTD, showing how the kinetics of the NR2A subunits expressed by parallel fibers implement a high-pass filter plasticity rule that will selectively attenuate synapses undergoing high-frequency bursts of activity. Depending on the type of NMDA receptor subunit expressed, high-pass filters of different corner frequencies could be implemented at other synapses expressing NMDA autoreceptors.autoreceptors ͉ cerebellum ͉ LTD

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Section: Resultsmentioning

confidence: 92%

Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule

Bidoret¹,

Ayon²,

Barbour³

et al. 2009

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

136

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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%

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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“…7 and 8a). Given that Purkinje cells are thought to express relatively low amounts of functional NMDA receptors [4,21] and that only CF but not PF stimulation could induce an NMDA receptor current in PNs of adult rodents [32,34], while molecular layer interneurons are known for a rich expression of NMDA receptors [1,9], we propose that interneurons are the most likely source of NO for preLTP [33,39] and of endocannabinoids [6] for pre LTD. Of course, we cannot exclude that 4 Hz PF stimulation also activates NMDA and/or mGlu1 receptors on PNs to some degree resulting in some release of endocannabinoids. If the LTD observed in PNs that were patch-clamped with a high concentration of a Ca 2+ chelator (30 mM BAPTA) in the intracellular solution (Figs.…”

Section: Demonstration Of Preltdmentioning

confidence: 91%

Presynaptically expressed long-term depression at cerebellar parallel fiber synapses

Qiu

Knöpfel

2008

Pflugers Arch - Eur J Physiol

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Plasticity at synapses between parallel fiber (PF) and Purkinje neurons (PN) is widely accepted as a cellular model for certain forms of cerebellar learning. Although PF-PN synapses are known to express bidirectional longterm plasticity at the postsynaptic site, long-term plasticity at the presynaptic site is currently limited to potentiation of the synapses. In this paper, we report on presynaptically expressed PF long-term depression (preLTD) that is observed when presynaptically expressed PF long-term potentiation (preLTP) is pharmacologically prevented. PF preLTD is most efficiently induced by 4 Hz PF stimulation and requires activation of cannabinoid CB1 receptors. Our results indicate that, during preLTD induction, endocannabinoids are released in an NMDA receptor-dependent, but not mGlu1 receptor-dependent, fashion. We conclude that bidirectional plasticity mechanisms exist for both presynaptic and postsynaptic components of cerebellar learning.

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NMDA Receptor Contribution to the Climbing Fiber Response in the Adult Mouse Purkinje Cell

Cited by 108 publications

References 69 publications

Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule

Presynaptic NR2A-containing NMDA receptors implement a high-pass filter synaptic plasticity rule

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

Presynaptically expressed long-term depression at cerebellar parallel fiber synapses

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