1. Neuroscience
Download icon

Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity

  1. Amy E Pohodich
  2. Hari Yalamanchili
  3. Ayush T Raman
  4. Ying-Wooi Wan
  5. Michael Gundry
  6. Shuang Hao
  7. Haijing Jin
  8. Jianrong Tang
  9. Zhandong Liu
  10. Huda Y Zoghbi  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. Texas Children's Hospital, United States
Research Article
  • Cited 18
  • Views 2,574
  • Annotations
Cite this article as: eLife 2018;7:e34031 doi: 10.7554/eLife.34031

Abstract

Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer's patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17-24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders.

Article and author information

Author details

  1. Amy E Pohodich

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  2. Hari Yalamanchili

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  3. Ayush T Raman

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  4. Ying-Wooi Wan

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  5. Michael Gundry

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.

  6. Shuang Hao

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  7. Haijing Jin

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  8. Jianrong Tang

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  9. Zhandong Liu

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    Competing interests
    No competing interests declared.

  10. Huda Y Zoghbi

    Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
    For correspondence
    hzoghbi@bcm.edu
    Competing interests
    Huda Y Zoghbi, Senior editor, eLifeis one of the co-holders of U.S. Patent 6,709,817 Method of Screening Rett Syndrome by Detecting a Mutation in MECP2, March 23, 2004.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0700-3349

Funding

National Institutes of Health (5R01NS057819)

  • Huda Y Zoghbi

Howard Hughes Medical Institute (HHMI Investigator)

  • Huda Y Zoghbi

Robert and Janice McNair Foundation (Student Scholar)

  • Amy E Pohodich

Baylor Research Advocates for Student Scientists (Student Scholar)

  • Amy E Pohodich

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All research and animal care procedures were approved by the Baylor College of Medicine Institutional Animal Care and Use Committee (approved protocols: AN-1013 and AN-5585). All surgery was performed under isofluorane anesthesia, and every effort was made to minimize pain and suffering.

Reviewing Editor

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

Publication history

  1. Received: December 4, 2017
  2. Accepted: March 22, 2018
  3. Accepted Manuscript published: March 23, 2018 (version 1)
  4. Version of Record published: April 18, 2018 (version 2)

Copyright

© 2018, Pohodich 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

  • 2,574
    Page views
  • 488
    Downloads
  • 18
    Citations

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

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)

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

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

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Brain endothelial cell TRPA1 channels initiate neurovascular coupling

    Pratish Thakore et al.
    Research Article Updated

    Cerebral blood flow is dynamically regulated by neurovascular coupling to meet the dynamic metabolic demands of the brain. We hypothesized that TRPA1 channels in capillary endothelial cells are stimulated by neuronal activity and instigate a propagating retrograde signal that dilates upstream parenchymal arterioles to initiate functional hyperemia. We find that activation of TRPA1 in capillary beds and post-arteriole transitional segments with mural cell coverage initiates retrograde signals that dilate upstream arterioles. These signals exhibit a unique mode of biphasic propagation. Slow, short-range intercellular Ca2+ signals in the capillary network are converted to rapid electrical signals in transitional segments that propagate to and dilate upstream arterioles. We further demonstrate that TRPA1 is necessary for functional hyperemia and neurovascular coupling within the somatosensory cortex of mice in vivo. These data establish endothelial cell TRPA1 channels as neuronal activity sensors that initiate microvascular vasodilatory responses to redirect blood to regions of metabolic demand.

    1. Neuroscience

    Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse

    Timothy S Balmer et al.
    Research Article Updated

    Synapses of glutamatergic mossy fibers (MFs) onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using mouse brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBCs. The source of this ambient glutamate was spontaneous, spike-independent exocytosis from the MF terminal, and its level was dependent on activity of glutamate transporters EAAT1–2. Increasing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.

    1. Developmental Biology
    2. Neuroscience

    Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance

    Hiroki Takechi et al.
    Research Article

    Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.