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

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 sub...

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Bibliographic Details
Published in:Brain Structure and Function 2019-01, Vol.224 (1), p.471-483
Main Authors: Hill, Julia L., Jimenez, Dennisse V., Mai, Yishan, Ren, Ming, Hallock, Henry L., Maynard, Kristen R., Chen, Huei-Ying, Hardy, Nicholas F., Schloesser, Robert J., Maher, Brady J., Yang, Feng, Martinowich, Keri
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal
Biomedical and Life Sciences
Biomedicine
Brain - metabolism
Brain - physiopathology
Brain Waves
Brain-derived neurotrophic factor
Brain-Derived Neurotrophic Factor - metabolism
Cell Biology
Cortex
Epilepsy
Excitability
Excitatory Postsynaptic Potentials
Hippocampus
Hyperkinesis - metabolism
Hyperkinesis - physiopathology
Hyperkinesis - prevention & control
Hyperkinesis - psychology
Interneurons
Interneurons - metabolism
Locomotion
Membrane Glycoproteins - deficiency
Membrane Glycoproteins - genetics
Membrane Glycoproteins - metabolism
Mice, Inbred C57BL
Mice, Knockout
Neural Inhibition
Neurology
Neuropeptides - deficiency
Neuropeptides - genetics
Neuropeptides - metabolism
Neurosciences
Original Article
Protein-Tyrosine Kinases - deficiency
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
Receptor mechanisms
Seizures
Seizures - metabolism
Seizures - physiopathology
Seizures - prevention & control
Seizures - psychology
Sleep
Synaptic Transmission
TrkB receptors
Tropomyosin
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Summary: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.
ISSN:1863-2653
1863-2661
0340-2061
DOI:10.1007/s00429-018-1783-1