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Brain Structure and Function

, Volume 224, Issue 1, pp 471–483 | Cite as

Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability

  • Julia L. Hill
  • Dennisse V. Jimenez
  • Yishan Mai
  • Ming Ren
  • Henry L. Hallock
  • Kristen R. Maynard
  • Huei-Ying Chen
  • Nicholas F. Hardy
  • Robert J. Schloesser
  • Brady J. Maher
  • Feng Yang
  • Keri MartinowichEmail author
Original Article

Abstract

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

Keywords

BDNF TrkB Interneuron Seizure Sleep Cortistatin 

Notes

Acknowledgements

We thank Dr. Daniel Weinberger and members of the Martinowich laboratory for critical reading of the manuscript.

Funding

This work was supported by the National Institutes of Health (MH105592 to KM); the Epilepsy Foundation (Research Grant to KM); and the Lieber Institute for Brain Development.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

429_2018_1783_MOESM1_ESM.pdf (1.6 mb)
Supplementary material 1 (PDF 1623 KB)

Supplementary material 2 (MP4 44307 KB)

Supplementary material 3 (MP4 44413 KB)

Supplementary material 4 (MP4 44403 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Julia L. Hill
    • 1
  • Dennisse V. Jimenez
    • 1
  • Yishan Mai
    • 1
  • Ming Ren
    • 1
  • Henry L. Hallock
    • 1
  • Kristen R. Maynard
    • 1
  • Huei-Ying Chen
    • 1
  • Nicholas F. Hardy
    • 1
  • Robert J. Schloesser
    • 2
  • Brady J. Maher
    • 1
    • 3
  • Feng Yang
    • 1
  • Keri Martinowich
    • 1
    • 3
    Email author
  1. 1.Lieber Institute for Brain DevelopmentJohns Hopkins Medical CampusBaltimoreUSA
  2. 2.Sheppard Pratt-Lieber Research Institute, IncBaltimoreUSA
  3. 3.Departments of Psychiatry and Behavioral Sciences, and NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

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