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

Brain Struct Funct. 2019 Jan;224(1):471-483. doi: 10.1007/s00429-018-1783-1. Epub 2018 Oct 30.


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; Cortistatin; Interneuron; Seizure; Sleep; TrkB.

MeSH terms

  • Animals
  • Behavior, Animal*
  • Brain / metabolism*
  • Brain / physiopathology
  • Brain Waves*
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Excitatory Postsynaptic Potentials
  • Hyperkinesis / metabolism*
  • Hyperkinesis / physiopathology
  • Hyperkinesis / prevention & control
  • Hyperkinesis / psychology
  • Interneurons / metabolism*
  • Locomotion*
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition
  • Neuropeptides / deficiency
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Seizures / metabolism*
  • Seizures / physiopathology
  • Seizures / prevention & control
  • Seizures / psychology
  • Sleep
  • Synaptic Transmission*


  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor
  • Membrane Glycoproteins
  • Neuropeptides
  • cortistatin
  • Ntrk2 protein, mouse
  • Protein-Tyrosine Kinases