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

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

Author information

1
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
2
Sheppard Pratt-Lieber Research Institute, Inc, Baltimore, MD, 21204, USA.
3
Departments of Psychiatry and Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
4
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA. keri.martinowich@libd.org.
5
Departments of Psychiatry and Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. keri.martinowich@libd.org.

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; Cortistatin; Interneuron; Seizure; Sleep; TrkB

PMID:
30377803
PMCID:
PMC6613949
DOI:
10.1007/s00429-018-1783-1
[Indexed for MEDLINE]
Free PMC Article

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