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 Martinowich

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)471-483
Number of pages13
JournalBrain Structure and Function
Volume224
Issue number1
DOIs
StatePublished - Jan 15 2019

Keywords

  • BDNF
  • Cortistatin
  • Interneuron
  • Seizure
  • Sleep
  • TrkB

ASJC Scopus subject areas

  • Anatomy
  • Neuroscience(all)
  • Histology

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