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

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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.

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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.

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Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA

    Julia L. Hill, Dennisse V. Jimenez, Yishan Mai, Ming Ren, Henry L. Hallock, Kristen R. Maynard, Huei-Ying Chen, Nicholas F. Hardy, Brady J. Maher, Feng Yang & Keri Martinowich

  2. Sheppard Pratt-Lieber Research Institute, Inc, Baltimore, MD, 21204, USA

    Robert J. Schloesser

  3. Departments of Psychiatry and Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher & Keri Martinowich

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  1. Julia L. Hill
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  2. Dennisse V. Jimenez
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  3. Yishan Mai
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  4. Ming Ren
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  11. Feng Yang
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  12. Keri Martinowich
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Correspondence to Keri Martinowich.

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Hill, J.L., Jimenez, D.V., Mai, Y. et al. Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability. Brain Struct Funct 224, 471–483 (2019). https://doi.org/10.1007/s00429-018-1783-1

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