Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate

Abstract

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

Data availability

All raw data is plotted in the figures. ICP data and code (Figure 10) is included in a .zip file. Code for the analysis of actograms is available here: https://github.com/DrewLab/MedAssociates_WheelActivity

Article and author information

Author details

  1. Jordan N Norwood

    Cellular and Developmental Biology Graduate Program, Pennsylvania State University, University Park, United States
    For correspondence
    jnn120@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Qingguang Zhang

    Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4500-813X
  3. David Card

    Department of Physics, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amanda Craine

    Department of Biomedical Engineering, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Timothy M Ryan

    Department of Anthropology, Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Patrick J Drew

    Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, United States
    For correspondence
    pjd17@psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7483-7378

Funding

National Science Foundation (CBET1705854)

  • Patrick J Drew

National Institutes of Health (F31NS105461)

  • Jordan N Norwood

McKnight Endowment Fund for Neuroscience

  • Patrick J Drew

National Institutes of Health (R01NS078168)

  • Patrick J Drew

National Institutes of Health (P01HD078233)

  • Patrick J Drew

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

Ethics

Animal experimentation: The protocols used in this study were approved by the Institutional Animal Care and Use Committee (IACUC) at the Pennsylvania State University

Copyright

© 2019, Norwood 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

  • 6,616
    views
  • 804
    downloads
  • 94
    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. Jordan N Norwood
  2. Qingguang Zhang
  3. David Card
  4. Amanda Craine
  5. Timothy M Ryan
  6. Patrick J Drew
(2019)
Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate
eLife 8:e44278.
https://doi.org/10.7554/eLife.44278

Share this article

https://doi.org/10.7554/eLife.44278

Further reading

    1. Neuroscience
    Christopher Bell, Lukas Kilo ... Stefanie Ryglewski
    Research Article

    At many vertebrate synapses, presynaptic functions are tuned by expression of different Cav2 channels. Most invertebrate genomes contain only one Cav2 gene. The Drosophila Cav2 homolog, cacophony (cac), induces synaptic vesicle release at presynaptic active zones (AZs). We hypothesize that Drosophila cac functional diversity is enhanced by two mutually exclusive exon pairs that are not conserved in vertebrates, one in the voltage sensor and one in the loop binding Caβ and Gβγ subunits. We find that alternative splicing in the voltage sensor affects channel activation voltage. Only the isoform with the higher activation voltage localizes to AZs at the glutamatergic Drosophila larval neuromuscular junction and is imperative for normal synapse function. By contrast, alternative splicing at the other alternative exon pair tunes multiple aspects of presynaptic function. While expression of one exon yields normal transmission, expression of the other reduces channel number in the AZ and thus release probability. This also abolishes presynaptic homeostatic plasticity. Moreover, reduced channel number affects short-term plasticity, which is rescued by increasing the external calcium concentration to match release probability to control. In sum, in Drosophila alternative splicing provides a mechanism to regulate different aspects of presynaptic functions with only one Cav2 gene.

    1. Neuroscience
    2. Structural Biology and Molecular Biophysics
    Yangyu Wu, Yangyang Yan ... Fred J Sigworth
    Research Article

    We present near-atomic-resolution cryoEM structures of the mammalian voltage-gated potassium channel Kv1.2 in open, C-type inactivated, toxin-blocked and sodium-bound states at 3.2 Å, 2.5 Å, 3.2 Å, and 2.9 Å. These structures, all obtained at nominally zero membrane potential in detergent micelles, reveal distinct ion-occupancy patterns in the selectivity filter. The first two structures are very similar to those reported in the related Shaker channel and the much-studied Kv1.2–2.1 chimeric channel. On the other hand, two new structures show unexpected patterns of ion occupancy. First, the toxin α-Dendrotoxin, like Charybdotoxin, is seen to attach to the negatively-charged channel outer mouth, and a lysine residue penetrates into the selectivity filter, with the terminal amine coordinated by carbonyls, partially disrupting the outermost ion-binding site. In the remainder of the filter two densities of bound ions are observed, rather than three as observed with other toxin-blocked Kv channels. Second, a structure of Kv1.2 in Na+ solution does not show collapse or destabilization of the selectivity filter, but instead shows an intact selectivity filter with ion density in each binding site. We also attempted to image the C-type inactivated Kv1.2 W366F channel in Na+ solution, but the protein conformation was seen to be highly variable and only a low-resolution structure could be obtained. These findings present new insights into the stability of the selectivity filter and the mechanism of toxin block of this intensively studied, voltage-gated potassium channel.