1. Neuroscience
Download icon

Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

  1. Achira Roy
  2. Jonathan Skibo
  3. Franck Kalume
  4. Jing Ni
  5. Sherri Rankin
  6. Yiling Lu
  7. William B Dobyns
  8. Gordon B Mills
  9. Jean J Zhao
  10. Suzanne J Baker
  11. Kathleen J Millen  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. Dana Farber Cancer Institute, United States
  3. St. Jude Children's Research Hospital, United States
  4. The University of Texas MD Anderson Cancer Center, United States
Research Article
  • Cited 38
  • Views 3,252
  • Annotations
Cite this article as: eLife 2015;4:e12703 doi: 10.7554/eLife.12703

Abstract

Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1hour-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.

Article and author information

Author details

  1. Achira Roy

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jonathan Skibo

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Franck Kalume

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jing Ni

    Department of Cancer biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sherri Rankin

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yiling Lu

    The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. William B Dobyns

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gordon B Mills

    The University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean J Zhao

    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Suzanne J Baker

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Kathleen J Millen

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    kathleen.millen@seattlechildrens.org
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal experimentation done in this study was done in accordance with the guidelines laid down by the Institutional Animal Care and Use Committees (IACUC) of Seattle Children's Research Institute, Seattle, WA (protocol 14208), St. Jude Children's Research Hospital, Memphis, TN (protocol 278), Dana Farber Cancer Institute, Boston, MA (protocol 06-034).

Reviewing Editor

  1. Sean J Morrison, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: October 29, 2015
  2. Accepted: November 26, 2015
  3. Accepted Manuscript published: December 3, 2015 (version 1)
  4. Version of Record published: January 27, 2016 (version 2)

Copyright

© 2015, Roy 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

  • 3,252
    Page views
  • 684
    Downloads
  • 38
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, 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)

Further reading

    1. Neuroscience
    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
    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.