Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Journal Club

The Calcium Kinetics and Inositol Trisphosphate Receptor Properties Shape the Asymmetric Timing Window of Coincidence Detection

Hideaki Ogasawara
Journal of Neuroscience 23 April 2008, 28 (17) 4293-4294; DOI: https://doi.org/10.1523/JNEUROSCI.0644-08.2008
Hideaki Ogasawara
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • eLetters
  • PDF
Loading

The cerebellum is thought to be a specialized organ for supervised learning (also known as associative learning), through which each input signal is specifically associated with a desired output. Purkinje cells provide the sole output from the cerebellar cortex, and each Purkinje cell receives two types of excitatory inputs: one from hundreds of thousands of parallel fibers and the other from a single climbing fiber. The transmission efficacy of the parallel fiber–Purkinje cell synapse is depressed when the climbing fiber and parallel fiber are repetitively and synchronously activated [long-term depression (LTD)]. This spike-timing-dependent plasticity is widely accepted as the cellular correlate of cerebellar associative learning.

Parallel fibers and climbing fibers activate different signaling pathways in Purkinje cells. On the one hand, parallel fiber firing activates the mGluR1 metabotropic glutamate receptor pathway, resulting in activation of phospholipase C (PLC) and production of inositol 1,4,5-trisphosphate (IP3). However, climbing fiber firing depolarizes the Purkinje cell and induces Ca2+ influx through voltage-gated calcium channels. Therefore, IP3 and Ca2+ represent parallel-fiber and climbing-fiber activities, respectively. By sensing sequential binding of IP3 and Ca2+, the IP3 receptor acts as a coincidence detector that associates parallel fiber inputs with climbing fiber inputs. The output signal is the release of more Ca2+ from internal stores, which leads to LTD (Wang et al., 2000; Doi et al., 2005). IP3 receptor-mediated calcium-induced calcium release is greatest when parallel fiber stimuli precede climbing fiber stimuli by ∼100 ms (half-maximal width, ∼200 ms).

The characteristics of the IP3 receptor that shape the timing window of coincidence detection are not fully understood. To answer this question, Sarkisov and Wang (2008) explored the coincidence detector properties of the IP3 receptor in Purkinje cells by photolyzing double-caged IP3, which is less antagonistic to the IP3 receptor and offers a higher spatial resolution of focal uncaging than its single-caged counterpart (Sarkisov et al., 2007). Coincident presentation of IP3 and climbing fiber activation triggered calcium signals in Purkinje cells that were substantially larger than the linear sum of the signals from climbing fiber and IP3 alone [Sarkisov and Wang (2008), their Fig. 1 (http://www.jneurosci.org/cgi/content/full/28/1/133/F1)]. Climbing fiber activation up to 100 ms before or up to 500 ms after IP3 uncaging resulted in synergistic calcium release [Sarkisov and Wang (2008), their Fig. 2 (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)]. Calcium responses were sensitive to the order of IP3 uncaging and climbing fiber activation, and the maximal signals were observed when the climbing fiber was activated 100–200 ms after IP3 uncaging; they reached 0.6–1.8 μm in spines and 0.3–0.7 μm in spiny dendrites [Sarkisov and Wang (2008), their Figs. 1D (http://www.jneurosci.org/cgi/content/full/28/1/133/F1), 2C,D (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)]. This optimal delay of climbing fiber inputs is consistent with their putative role in associative learning as teaching signals. Coincidence-dependent supralinearity emerged in a shorter time than enzymatic reactions take [Sarkisov and Wang (2008), their Fig. 3 (http://www.jneurosci.org/cgi/content/full/28/1/133/F3)], which, in agreement with previous simulation studies (Doi et al., 2005; Hernjak et al., 2005), suggests that PLC is not involved in the positive feedback loop of calcium-induced calcium release.

Next, by using a calcium-store depletor and an IP3 receptor blocker, the authors demonstrated that supralinear calcium signals resulted from IP3 receptor-mediated calcium-induced calcium release from internal stores [Sarkisov and Wang (2008), their Fig. 4D (http://www.jneurosci.org/cgi/content/full/28/1/133/F4)], as reported previously (Wang et al., 2000). To rule out the possibility that IP3-induced calcium release activates potassium conductance and enhances climbing fiber-evoked calcium entry to the hyperpolarized dendrite, they visualized calcium signals along the dendrite. As expected, the spatial distribution of supralinear calcium responses was much more restricted than that of electrical potentials [Sarkisov and Wang (2008), their Fig. 4 (http://www.jneurosci.org/cgi/content/full/28/1/133/F4)], indicating that potassium conductances are unlikely to be responsible for the supralinearity.

Calcium is stimulatory to the IP3 receptor at low concentrations, whereas it is inhibitory at high concentrations (Iino, 1990). Therefore, to test whether climbing fiber-evoked calcium influx had positive or negative effects on calcium release from internal stores, the authors measured calcium signals after stimulating the climbing fiber variable times and photolyzing IP3 at the end of the stimuli [Sarkisov and Wang (2008), their Fig. 5 (http://www.jneurosci.org/cgi/content/full/28/1/133/F5)]. The more times the climbing fiber was stimulated, the greater amount of calcium was released from internal stores, indicating that the climbing fiber-evoked calcium responses in their experimental settings were within a range that stimulates the IP3 receptor.

The IP3-before-climbing-fiber timing window of several hundred milliseconds [Sarkisov and Wang (2008), their Fig. 2C,D (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)] is similar to the binding dissociation time of IP3 from its receptor, suggesting that the timing window is defined by this dissociation. IP3 degradation also might shape the timing window, although some theoretical studies have indicated that it is unlikely (Doi et al., 2005; Hernjak et al., 2005). To experimentally rule out IP3 degradation as a timing window constraint, the authors took advantage of a poorly hydrolyzable agonist of the IP3 receptor, gPIP2. gPIP2 uncaging at two time points revealed that the size of paired-pulse enhancement was a monotonically decreasing function of the interval, with a half-maximal width of 400 ms, which corresponded to the binding dissociation timescale [Sarkisov and Wang (2008), their Fig. 6 (http://www.jneurosci.org/cgi/content/full/28/1/133/F6)]. This finding supports the previous hypothesis that the timing window was set by dissociation of IP3 from its receptor, not by IP3 degradation.

Collectively, these remarkable experiments indicate that the asymmetric timing window of coincidence detection in the Purkinje cell is shaped by the calcium kinetics and IP3 receptor properties; but some intriguing questions still need to be answered. First, could LTD be induced in a coincidence-dependent manner by the coincident activation protocol the authors used? If and only if so, coincidence signals explored in this study could be discussed in the context of spike-timing-dependent plasticity mechanisms. The above question arises because IP3 uncaging and climbing fiber activation resulted in supralinear calcium signals [Sarkisov and Wang (2008), their Fig. 1 (http://www.jneurosci.org/cgi/content/full/28/1/133/F1)] that were considerably smaller (<2 μm) than those resulting from conjunctive parallel-fiber–climbing-fiber activation (>10 μm) (Wang et al., 2000). Although the authors cite another study indicating that 2 μm of calcium was sufficient for LTD induction (Tanaka et al., 2007), in that study, LTD required a sustained calcium increase lasting for more than several seconds. Thus, the calcium transients that decayed within hundreds of milliseconds in Sarkisov and Wang (2008) may not have been sufficient to produce LTD.

The second remaining question concerns the order dependence of the peak supralinearity. The authors observed maximal supralinearity at Δt = ∼100 ms [Sarkisov and Wang (2008), their Fig. 2C,D (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)]. But if the timing window were shaped solely by the calcium kinetics and IP3 receptor–IP3 dissociation profile, the supralinearity should have been largest when IP3 uncaging and climbing fiber activation were exactly coincident, leading to a simultaneous rise of IP3 and Ca2+ concentrations and the most efficient activation of the IP3 receptor. In other words, the difference in rate between calcium decay and binding dissociation of IP3 from its receptor [Sarkisov and Wang (2008), their Fig. 7 (http://www.jneurosci.org/cgi/content/full/28/1/133/F7)] only accounts for the difference in slopes on the left and right sides of each asymmetric supralinearity plot [Sarkisov and Wang (2008), their Fig. 2C,D (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)], leaving the deviation of its peak from the exact point of coincidence unexplained. UV-induced IP3 photolysis and climbing fiber-induced calcium influx are fast processes that take place and affect the intracellular Ca2+ concentrations within 10–20 ms [Sarkisov and Wang (2008), their Figs. 1C (http://www.jneurosci.org/cgi/content/full/28/1/133/F1), 6A (http://www.jneurosci.org/cgi/content/full/28/1/133/F6)], and their timing does not account for the shift of the peak, either. In addition to the lack of explanatory factors for the order-dependence of the maximal supralinearity, the order-dependence itself is unclear. Fitting a Gaussian distribution to an asymmetric plot [as was done in this study Sarkisov and Wang (2008), their Fig. 2C,D (http://www.jneurosci.org/cgi/content/full/28/1/133/F2)] can lead to erroneous statistical conclusions as well as a misinterpretation of the peak location. Considering that, it might be better not to reject for now the null hypothesis that the peak of the supralinearity lies at Δt = 0.

Footnotes

  • I thank Kelvin So for helpful comments on this manuscript.

  • Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

  • Correspondence should be addressed to Hideaki Ogasawara, National Institute of Information and Communications Technology, 2-2-2, Hikaridai, Seika, 619-0288 Kyoto, Japan. h_ogasawara{at}nict.go.jp

References

  1. ↵
    1. Doi T,
    2. Kuroda S,
    3. Michikawa T,
    4. Kawato M
    (2005) Inositol 1,4,5-trisphosphate-dependent Ca2+ threshold dynamics detect spike timing in cerebellar Purkinje cells. J Neurosci 25:950–961.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Hernjak N,
    2. Slepchenko BM,
    3. Fernald K,
    4. Fink CC,
    5. Fortin D,
    6. Moraru II,
    7. Watras J,
    8. Loew LM
    (2005) Modeling and analysis of calcium signaling events leading to long-term depression in cerebellar Purkinje cells. Biophys J 89:3790–3806.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Iino M
    (1990) Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca release in smooth muscle cells of the guinea pig Taenia caeci. J Gen Physiol 95:1103–1122.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Sarkisov DV,
    2. Wang SS
    (2008) Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor. J Neurosci 28:133–142.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Sarkisov DV,
    2. Gelber SE,
    3. Walker JW,
    4. Wang SS
    (2007) Synapse specificity of calcium release probed by chemical two-photon uncaging of inositol 1,4,5-trisphosphate. J Biol Chem 282:25517–25526.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Tanaka K,
    2. Khiroug L,
    3. Santamaria F,
    4. Doi T,
    5. Ogasawara H,
    6. Ellis-Davies GC,
    7. Kawato M,
    8. Augustine GJ
    (2007) Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron 54:787–800.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Wang SS,
    2. Denk W,
    3. Häusser M
    (2000) Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci 3:1266–1273.
    OpenUrlCrossRefPubMed
Back to top

In this issue

The Journal of Neuroscience: 28 (17)
Journal of Neuroscience
Vol. 28, Issue 17
23 Apr 2008
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
The Calcium Kinetics and Inositol Trisphosphate Receptor Properties Shape the Asymmetric Timing Window of Coincidence Detection
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
The Calcium Kinetics and Inositol Trisphosphate Receptor Properties Shape the Asymmetric Timing Window of Coincidence Detection
Hideaki Ogasawara
Journal of Neuroscience 23 April 2008, 28 (17) 4293-4294; DOI: 10.1523/JNEUROSCI.0644-08.2008

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
The Calcium Kinetics and Inositol Trisphosphate Receptor Properties Shape the Asymmetric Timing Window of Coincidence Detection
Hideaki Ogasawara
Journal of Neuroscience 23 April 2008, 28 (17) 4293-4294; DOI: 10.1523/JNEUROSCI.0644-08.2008
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Info & Metrics
  • eLetters
  • PDF

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

  • Role of Neurexins in Alzheimer's Disease
  • Objects from Motion: Moving beyond Static Images with Object Kinematograms
  • Toward an Interpersonal Neuroscience in Technologically Assisted (Virtual) Interactions
Show more Journal Club
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2023 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.