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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We thank Dr. Daniel Weinberger and members of the Martinowich laboratory for critical reading of the manuscript.
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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The authors declare that they have no conflict of interest.
All applicable international, national and/or institutional guidelines for the care and use of animals were followed.
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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