Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons

  1. Lauren Tereshko
  2. Ya Gao
  3. Brian A Cary
  4. Gina G Turrigiano  Is a corresponding author
  5. Piali Sengupta  Is a corresponding author
  1. Brandeis University, United States

Abstract

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all relevant figures.

Article and author information

Author details

  1. Lauren Tereshko

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  2. Ya Gao

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9608-8988
  3. Brian A Cary

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1759-164X
  4. Gina G Turrigiano

    Department of Biology, Brandeis University, Waltham, United States
    For correspondence
    turrigiano@brandeis.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4476-4059
  5. Piali Sengupta

    Department of Biology, Brandeis University, Waltham, United States
    For correspondence
    sengupta@brandeis.edu
    Competing interests
    Piali Sengupta, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7468-0035

Funding

National Institute of General Medical Sciences (R35 GM122463)

  • Piali Sengupta

National Institute of Mental Health (R21 MH118464)

  • Gina G Turrigiano
  • Piali Sengupta

National Institute of Neurological Disorders and Stroke (R35 NS111562)

  • Gina G Turrigiano

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

Ethics

Animal experimentation: All experimental procedures were approved by the the Brandeis University IACUC (IACUC protocol # 18002) and were performed according to NIH guidelines.

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: December 3, 2020
  2. Accepted: March 1, 2021
  3. Accepted Manuscript published: March 2, 2021 (version 1)
  4. Version of Record published: March 11, 2021 (version 2)

Copyright

© 2021, Tereshko 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

  • 1,900
    Page views
  • 253
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Lauren Tereshko
  2. Ya Gao
  3. Brian A Cary
  4. Gina G Turrigiano
  5. Piali Sengupta
(2021)
Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons
eLife 10:e65427.
https://doi.org/10.7554/eLife.65427

Further reading

    1. Cell Biology
    Desiree Schatton et al.
    Research Article

    Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.

    1. Cell Biology
    Dillon Jevon et al.
    Research Article

    A developing understanding suggests that spatial compartmentalisation in pancreatic β cells is critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell sub-cellular imaging methods using the mouse organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact β cell structure, and enhances glucose dependent Ca2+ responses and insulin secretion. Using the slice technique, we have discovered the essential role of local activation of integrins and the downstream component, focal adhesion kinase, in regulating β cells. Integrins and focal adhesion kinase are exclusively activated at the β cell capillary interface and using in situ and in vitro models we show their activation both positions presynaptic scaffold proteins, like ELKS and liprin, and regulates glucose dependent Ca2+ responses and insulin secretion. We conclude that focal adhesion kinase orchestrates the final steps of glucose dependent insulin secretion within the restricted domain where β cells contact the islet capillaries.