Local dendritic Ca2+ signaling induces cerebellar long-term depression.

Eilers, Jens; Takechi, Hajime; Finch, Elizabeth A.; Augustine, George J; Konnerth, Arthur

doi:10.1101/lm.4.1.159

Cited by 53 publications

(29 citation statements)

References 42 publications

(51 reference statements)

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“…Image acquisition was restricted to the first 2 s of each beginning minute of ongoing stimulation to reduce the amount of phototoxicity. This strategy allowed us to monitor baseline and peak calcium levels during tetanization while minimizing transient calcium build-up that may result from prolonged light exposure [compare with studies that focused on capturing the complete calcium profile during ongoing tetanization (48,49)]. Our recordings show that under these imaging conditions, baseline calcium levels do not plateau.…”

Section: Methodsmentioning

confidence: 74%

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: Methodsmentioning

confidence: 74%

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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“…Additionally, without NO or Ca 2ϩ elevation, a small peak in the phosphorylation of the AMPA receptors could still be observed in the kinetic simulation (Fig. 5A), whereas this initial peak was not observed by the addition of blockers of Ca 2ϩ (Sakurai, 1990;Eilers et al, 1997) or NO (Lev-Ram et al, 1997). These discrepancies raise the possibility that other mechanisms underlie the expression of the initial phase of cerebellar LTD.…”

Section: Discussionmentioning

confidence: 99%

Exploration of Signal Transduction Pathways in Cerebellar Long-Term Depression by Kinetic Simulation

Kuroda

Schweighofer²,

Kawato³

2001

J. Neurosci.

123

141

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Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinasedependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.

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“…Conversely, strongly supralinear branchlet-wide [Ca 2+ ] responses could be evoked if the CF input were replaced by a somatic depolarizing current pulse (+0.4 nA, 50 ms). Such conditions are often used to evoke LTD in Purkinje cells 4,27,28 . Because depolarization can be used as a surrogate for CF activation of AMPA receptors 16 , we could test the ability of the AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) to block branchlet coincidence signals mediated by PF activation.…”

Section: Supralinear Calcium Signalsmentioning

confidence: 99%

Coincidence detection in single dendritic spines mediated by calcium release

2000

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articlesCentral to understanding learning mechanisms at a synaptic level is the idea that lasting functional change can be driven by the coincidence of multiple signals at a single synaptic site 1 . One candidate for such a change is long-term depression of the parallel fiber input to cerebellar Purkinje cells, a form of synaptic plasticity that is thought to underlie several forms of associative motor learning 2 . LTD is induced by coincident activation of PF and CF synaptic inputs, and can last from hours to days 2,3 .Although LTD has been extensively studied, the identity of the coincidence detection mechanism(s) triggered by conjunctive activation of PF and CF synapses is still controversial 4 . One second messenger, cytosolic calcium (Ca 2+ ), is both necessary 5 and sufficient 6 (L. Khiroug, G. Ellis-Davies & G. J. Augustine, Soc. Neurosci. Abstr. 25, 397.3, 1999) to induce a depression of synaptic strength. This indicates that Ca 2+ is a critical link in the induction of LTD. However, in contrast to most other synapses that show Ca 2+ -dependent associative plasticity, PF synapses lack postsynaptic NMDA receptors, which allow Ca 2+ to enter neurons in response to the simultaneous presence of glutamate and depolarization (for review, see ref. 1).Purkinje cells do, however, possess two other molecular mechanisms that could detect conjunctive PF and CF activation to generate a Ca 2+ signal. The first of these is the inositol-1,4, 5-trisphosphate (IP 3 ) receptor 7 , which is synergistically coactivated 8 by IP 3 and Ca 2+ . The IP 3 receptor controls Ca 2+ release from the endoplasmic reticulum and is present in high concentrations in both spines and shafts of Purkinje cell dendrites 9 . IP 3 could be formed via the activation of metabotropic glutamate receptors (mGluR) by glutamate released from PF terminals 10-12 . The source of Ca 2+ could be voltage-gated Ca 2+ channels, which are known to be located on PF spines 13 , and may even be colocalized with the IP 3 receptor on a molecular scale 14 . The depolarization necessary for activation of these Ca 2+ channels could be provided by the complex spike that is triggered by CF input 15 . This mechanism, therefore, predicts that the combination of CF and PF inputs should generate a supralinear Ca 2+ signal in PF spines 7 .A second potential coincidence detection mechanism uses the voltage-gated Ca 2+ channels in PF spines 13 . Because the channel activation curve is highly nonlinear, even a small local depolarization resulting from activation of AMPA channels at the PF synapse 16 could combine with the depolarization by the complex spike to cause supralinear Ca 2+ influx.The involvement of release through IP 3 receptors in the LTD induction pathway is supported by experiments demonstrating that blockers of Ca 2+ release inhibit LTD 6 , and that IP 3 uncaging can cause a form of LTD 6,11 . The metabotropic pathway is implicated because LTD induction can be prevented by mGluR antagonists 17 (but see also ref. 4), and is impaired in a genetic knockout of mGluR1 ...

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Local dendritic Ca2+ signaling induces cerebellar long-term depression.

Cited by 53 publications

References 42 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

Exploration of Signal Transduction Pathways in Cerebellar Long-Term Depression by Kinetic Simulation

Coincidence detection in single dendritic spines mediated by calcium release

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