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Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy

Abstract

Dysfunction of fast-spiking, parvalbumin-positive (FS-PV) interneurons is implicated in the pathogenesis of epilepsy. ErbB4, a key Neuregulin 1 (NRG1) receptor, is mainly expressed in this type of interneurons, and recent studies suggest that parvalbumin interneurons are a major target of NRG1-ErbB4 signaling in adult brain. Thus, we hypothesized that downregulation of NRG1-ErbB4 signaling in FS-PV interneurons is involved in epilepsy. We found that NRG1, through its receptor ErbB4, increased the intrinsic excitability of FS-PV interneurons. This effect was mediated by increasing the near-threshold responsiveness and decreasing the voltage threshold for action potentials through Kv1.1, a voltage-gated potassium channel. Furthermore, mice with specific deletion of ErbB4 in parvalbumin interneurons were more susceptible to pentylenetetrazole- and pilocarpine-induced models of epilepsy. Exogenous NRG1 delayed the onset of seizures and decreased their incidence and stage. Moreover, expression of ErbB4, but not ErbB2, was downregulated in human epileptogenic tissue. Together, our findings suggest that NRG1–ErbB4 signaling contributes to human epilepsy through regulating the excitability of FS-PV interneurons. ErbB4 may be a new target for anticonvulsant drugs in epilepsy.

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Figure 1: Both exogenous and endogenous NRG1 increase the excitability of cortical and hippocampal FS-PV interneurons.
Figure 2: Ablation of ErbB4 in parvalbumin neurons prevents NRG1 from increasing excitability of FS-PV interneurons.
Figure 3: Enhancement of initiation of action potential in FS-PV interneurons by NRG1.
Figure 4: Reversible increase of threshold current for action potential generation by ecto-ErbB4 and inhibition by DTx-K.
Figure 5: NRG1-ErbB4 signaling regulates Kv1.1 channels.
Figure 6: Decreased ErbB4 expression in human epileptogenic tissue.

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Acknowledgements

We thank L. Mei (Georgia Health Sciences University) for advice. We are grateful to T.M. Gao (Southern Medical University), Z.J. Huang (Cold Spring Harbor), X.H. Zhang (Institute of Neuroscience, Chinese Academy of Sciences) and L. Bao (Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences) for providing reagents and/or mice. We express our gratitude to the subjects and their families for their participation. We also thank T.M. Gao and I.C. Bruce for critical reading of this manuscript, and Q.L. Miao for technical assistance. This work was supported by grants from the National Natural Science Foundation of China (30970916, 31070926 and 30725047), the Major Research Program from the state Ministry of Science and Technology of China (2010CB912004, 2010CB912002), the Zhejiang Provincial Natural Science Foundation of China (Z2090127), the Foundation for the Author of National Excellent Doctoral Dissertation of China (200937), the Science Foundation of Chinese Universities (JD09023), the Zhejiang Provincial Qianjiang Talent Plan (2010R10057), the Fundamental Research Funds for the Central Universities (2011XZZX002) and Zhejiang Province Key Technology Innovation Team (2010R50049).

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K.-X.L. conducted the electrophysiological studies, analyzed data and wrote the manuscript; Y.-M.L. conducted the western blot analyses and wrote the manuscript; Z.-H.X. performed the studies on the mouse model of epilepsy and analyzed data; J.Z. performed the immunostaining experiments; J.-M. Zhu and J.-M. Zhang performed surgery, provided the human tissues and analyzed data; S.-X.C. conducted part of the electrophysiological recording and gene identification; X.-J.C. purified the compounds; Z.C., S.D. and J.-H.L. contributed experimental suggestions; X.-M.L. supervised all phases of the project and wrote the manuscript.

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Correspondence to Xiao-Ming Li.

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Li, KX., Lu, YM., Xu, ZH. et al. Neuregulin 1 regulates excitability of fast-spiking neurons through Kv1.1 and acts in epilepsy. Nat Neurosci 15, 267–273 (2012). https://doi.org/10.1038/nn.3006

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