1. Neuroscience

MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

  1. Özgür Genç
  2. Dion Kai Dickman
  3. Wenpei Ma
  4. Amy Tong
  5. Richard D Fetter
  6. Graeme W Davis  Is a corresponding author
  1. University of California, San Francisco, United States
  2. University of Southern California, United States
https://doi.org/10.7554/eLife.22904
Share this article
Cite this article
  1. Özgür Genç
  2. Dion Kai Dickman
  3. Wenpei Ma
  4. Amy Tong
  5. Richard D Fetter
  6. Graeme W Davis
(2017)
MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity
eLife 6:e22904.
https://doi.org/10.7554/eLife.22904
  2. Download BibTeX
  3. Download .RIS

Abstract

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.

Article and author information

Author details

  1. Özgür Genç

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  2. Dion Kai Dickman

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1884-284X

  3. Wenpei Ma

    Department of Biological Sciences, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.

  4. Amy Tong

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  5. Richard D Fetter

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  6. Graeme W Davis

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    graeme.davis@ucsf.edu
    Competing interests
    Graeme W Davis, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1355-8401

Funding

National Institute of Neurological Disorders and Stroke (NS039313)

  • Graeme W Davis

National Institutes of Neurological Disorders and Stroke (NS097212)

  • Graeme W Davis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Genç et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,145
    views
  • 511
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Özgür Genç
  2. Dion Kai Dickman
  3. Wenpei Ma
  4. Amy Tong
  5. Richard D Fetter
  6. Graeme W Davis
(2017)
MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity
eLife 6:e22904.
https://doi.org/10.7554/eLife.22904

Share this article

https://doi.org/10.7554/eLife.22904

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Spinal V1 inhibitory interneuron clades differ in birthdate, projections to motoneurons, and heterogeneity

    Andrew E Worthy, Joanna T Anderson ... Francisco J Alvarez
    Research Article

    Spinal cord interneurons play critical roles shaping motor output, but their precise identity and connectivity remain unclear. Focusing on the V1 interneuron cardinal class we defined four major V1 subsets in the mouse according to neurogenesis, genetic lineage-tracing, synaptic output to motoneurons, and synaptic inputs from muscle afferents. Sequential neurogenesis delineates different V1 subsets: two early born (Renshaw and Pou6f2) and two late born (Foxp2 and Sp8). Early born Renshaw cells and late born Foxp2-V1 interneurons are tightly coupled to motoneurons, while early born Pou6f2-V1 and late born Sp8-V1 interneurons are not, indicating that timing of neurogenesis does not correlate with motoneuron targeting. V1 clades also differ in cell numbers and diversity. Lineage labeling shows that the Foxp2-V1 clade contains over half of all V1 interneurons, provides the largest inhibitory input to motoneuron cell bodies, and includes subgroups that differ in birthdate, location, and proprioceptive input. Notably, one Foxp2-V1 subgroup, defined by postnatal Otp expression, is positioned near the LMC and receives substantial input from proprioceptors, consistent with an involvement in reciprocal inhibitory pathways. Combined tracing of ankle flexor sensory afferents and interneurons monosynaptically connected to ankle extensors confirmed placement of Foxp2-V1 interneurons in reciprocal inhibitory pathways. Our results validate previously proposed V1 clades as unique functional subtypes that differ in circuit placement, with Foxp2-V1 cells forming the most heterogeneous subgroup. We discuss how V1 organizational diversity enables understanding of their roles in motor control, with implications for their diverse ontogenetic and phylogenetic origins.

    1. Neuroscience

    Brain Activity: Unifying networks of a rhythm

    Mohsen Alavash
    Insight

    Combining electrophysiological, anatomical and functional brain maps reveals networks of beta neural activity that align with dopamine uptake.

    1. Neuroscience

    Evaluating hippocampal replay without a ground truth

    Masahiro Takigawa, Marta Huelin Gorriz ... Daniel Bendor
    Research Article

    During rest and sleep, memory traces replay in the brain. The dialogue between brain regions during replay is thought to stabilize labile memory traces for long-term storage. However, because replay is an internally-driven, spontaneous phenomenon, it does not have a ground truth - an external reference that can validate whether a memory has truly been replayed. Instead, replay detection is based on the similarity between the sequential neural activity comprising the replay event and the corresponding template of neural activity generated during active locomotion. If the statistical likelihood of observing such a match by chance is sufficiently low, the candidate replay event is inferred to be replaying that specific memory. However, without the ability to evaluate whether replay detection methods are successfully detecting true events and correctly rejecting non-events, the evaluation and comparison of different replay methods is challenging. To circumvent this problem, we present a new framework for evaluating replay, tested using hippocampal neural recordings from rats exploring two novel linear tracks. Using this two-track paradigm, our framework selects replay events based on their temporal fidelity (sequence-based detection), and evaluates the detection performance using each event's track discriminability, where sequenceless decoding across both tracks is used to quantify whether the track replaying is also the most likely track being reactivated.