1. Neuroscience

Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels

  1. Sharon Stevens
  2. Colleen M Longley
  3. Yuki Ogawa
  4. Lindsay Teliska
  5. Anithachristy Arumanayagam
  6. Supna Nair
  7. Juan A Oses-Prieto
  8. Alma L Burlingame
  9. Matthew Cykowski
  10. Mingshan Xue
  11. Matthew N Rasband  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Houston Methodist Hospital, United States
  3. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.66491
Share this article
Cite this article
  1. Sharon Stevens
  2. Colleen M Longley
  3. Yuki Ogawa
  4. Lindsay Teliska
  5. Anithachristy Arumanayagam
  6. Supna Nair
  7. Juan A Oses-Prieto
  8. Alma L Burlingame
  9. Matthew Cykowski
  10. Mingshan Xue
  11. Matthew N Rasband
(2021)
Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels
eLife 10:e66491.
https://doi.org/10.7554/eLife.66491
  2. Download BibTeX
  3. Download .RIS

Abstract

Neuronal ankyrins cluster and link membrane proteins to the actin and spectrin-based cytoskeleton. Among the three vertebrate ankyrins, little is known about neuronal Ankyrin-R (AnkR). We report AnkR is highly enriched in Pv+ fast-spiking interneurons in mouse and human. We identify AnkR-associated protein complexes including cytoskeletal proteins, cell adhesion molecules (CAMs), and perineuronal nets (PNNs). We show that loss of AnkR from forebrain interneurons reduces and disrupts PNNs, decreases anxiety-like behaviors, and changes the intrinsic excitability and firing properties of Pv+ fast-spiking interneurons. These changes are accompanied by a dramatic reduction in Kv3.1b K+ channels. We identify a novel AnkR-binding motif in Kv3.1b, and show that AnkR is both necessary and sufficient for Kv3.1b membrane localization in interneurons and at nodes of Ranvier. Thus, AnkR regulates Pv+ fast-spiking interneuron function by organizing ion channels, CAMs, and PNNs, and linking these to the underlying b1 spectrin-based cytoskeleton.

Data availability

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

Article and author information

Author details

  1. Sharon Stevens

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2238-8029

  2. Colleen M Longley

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8326-6143

  3. Yuki Ogawa

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Lindsay Teliska

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1733-6910

  5. Anithachristy Arumanayagam

    Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Supna Nair

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6499-0099

  7. Juan A Oses-Prieto

    Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4759-2341

  8. Alma L Burlingame

    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Matthew Cykowski

    Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Mingshan Xue

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1463-8884

  11. Matthew N Rasband

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    rasband@bcm.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8184-2477

Funding

National Institute of Neurological Disorders and Stroke (NS044916)

  • Matthew N Rasband

National Institute of General Medical Sciences (GM103481)

  • Alma L Burlingame

National Institute of Mental Health (MH117089)

  • Mingshan Xue

National Institute of Neurological Disorders and Stroke (NS100893)

  • Mingshan Xue

National Institute of Neurological Disorders and Stroke (NS100300)

  • Sharon Stevens

National Institute of Mental Health (MH118804)

  • Colleen M Longley

National Institute of Neurological Disorders and Stroke (NS118584)

  • Matthew Cykowski

Dr. Miriam and Sheldon G. Adelson Medical Research Foundation

  • Alma L Burlingame
  • Matthew N Rasband

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 experiments were conducted in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee at Baylor College of Medicine under approval AN4634.

Copyright

© 2021, Stevens 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

  • 2,253
    views
  • 370
    downloads
  • 37
    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. Sharon Stevens
  2. Colleen M Longley
  3. Yuki Ogawa
  4. Lindsay Teliska
  5. Anithachristy Arumanayagam
  6. Supna Nair
  7. Juan A Oses-Prieto
  8. Alma L Burlingame
  9. Matthew Cykowski
  10. Mingshan Xue
  11. Matthew N Rasband
(2021)
Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels
eLife 10:e66491.
https://doi.org/10.7554/eLife.66491

Share this article

https://doi.org/10.7554/eLife.66491

Categories and tags

Research organism

Further reading

    1. Medicine
    2. Neuroscience

    Hemispheric divergence of interoceptive processing across psychiatric disorders

    Emily M Adamic, Adam R Teed ... Sahib Khalsa
    Research Article

    Interactions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals. In contrast, during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e. when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Furthermore, the dysgranular mid-insula may indeed be a ‘locus of disruption’ for psychiatric disorders.

    1. Neuroscience

    CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction

    Natalia Mendes, Ariane Zanesco ... Licio A Velloso
    Research Article

    Microgliosis plays a critical role in diet-induced hypothalamic inflammation. A few hours after a high-fat diet (HFD), hypothalamic microglia shift to an inflammatory phenotype, and prolonged fat consumption leads to the recruitment of bone marrow-derived cells to the hypothalamus. However, the transcriptional signatures and functions of these cells remain unclear. Using dual-reporter mice, this study reveals that CX3CR1-positive microglia exhibit minimal changes in response to a HFD, while significant transcriptional differences emerge between microglia and CCR2-positive recruited myeloid cells, particularly affecting chemotaxis. These recruited cells also show sex-specific transcriptional differences impacting neurodegeneration and thermogenesis. The chemokine receptor CXCR3 is emphasized for its role in chemotaxis, displaying notable differences between recruited cells and resident microglia, requiring further investigation. Central immunoneutralization of CXCL10, a ligand for CXCR3, resulted in increased body mass and decreased energy expenditure, especially in females. Systemic chemical inhibition of CXCR3 led to significant metabolic changes, including increased body mass, reduced energy expenditure, elevated blood leptin, glucose intolerance, and decreased insulin levels. This study elucidates the transcriptional differences between hypothalamic microglia and CCR2-positive recruited myeloid cells in diet-induced inflammation and identifies CXCR3-expressing recruited immune cells as protective in metabolic outcomes linked to HFD consumption, establishing a new concept in obesity-related hypothalamic inflammation.

    1. Neuroscience

    A non-conducting role of the Cav1.4 Ca2+ channel drives homeostatic plasticity at the cone photoreceptor synapse

    J Wesley Maddox, Gregory J Ordemann ... Amy Lee
    Research Article

    In congenital stationary night blindness, type 2 (CSNB2)—a disorder involving the Cav1.4 (L-type) Ca2+ channel—visual impairment is mild considering that Cav1.4 mediates synaptic release from rod and cone photoreceptors. Here, we addressed this conundrum using a Cav1.4 knockout (KO) mouse and a knock-in (G369i KI) mouse expressing a non-conducting Cav1.4. Surprisingly, Cav3 (T-type) Ca2+ currents were detected in cones of G369i KI mice and Cav1.4 KO mice but not in cones of wild-type mouse, ground squirrels, and macaque retina. Whereas Cav1.4 KO mice are blind, G369i KI mice exhibit normal photopic (i.e. cone-mediated) visual behavior. Cone synapses, which fail to form in Cav1.4 KO mice, are present, albeit enlarged, and with some errors in postsynaptic wiring in G369i KI mice. While Cav1.4 KO mice lack evidence of cone synaptic responses, electrophysiological recordings in G369i KI mice revealed nominal transmission from cones to horizontal cells and bipolar cells. In CSNB2, we propose that Cav3 channels maintain cone synaptic output provided that the nonconducting role of Cav1.4 in cone synaptogenesis remains intact. Our findings reveal an unexpected form of homeostatic plasticity that relies on a non-canonical role of an ion channel.