Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons

Nature Neuroscience volume 15, pages 258–266 (2012)Cite this article

Subjects

Abstract

Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counterbalancing mechanisms. Using rodent models, here we show that limbic seizure activity upregulated NRG1–ErbB4 signaling and that epileptogenesis was inhibited by infusing NRG1 intracerebrally but exacerbated by neutralizing endogenous NRG1 with soluble ErbB4 extracellular domain, by inhibiting ErbB4 activation or by deleting the Erbb4 gene. Furthermore, specific depletion of ErbB4 in parvalbumin-expressing interneurons abolished NRG1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased spontaneous seizures and exuberant mossy fiber sprouting. In contrast, depleting ErbB4 in CaMKIIα-positive pyramidal neurons had no effect. Thus, NRG1-induced activation of ErbB4 in parvalbumin-expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Limbic seizure activity induces Nrg1 transcription and activation of the ErbB4 receptor in the rat brain.
Figure 2: Alteration of NRG1–ErbB4 signaling affects epileptogenesis in the rat kindling model.
Figure 3: Accelerated kindling progression in heart-rescued Erbb4 knockout mice.
Figure 4: Specific deletion of Erbb4 in parvalbumin-expressing neurons promotes kindling-induced epileptogenesis.
Figure 5: Ablation of Erbb4 in CaMKIIα-positive pyramidal neurons has no effect on kindling progression.
Figure 6: Specific ablation of Erbb4 in parvalbumin-expressing neurons increases kindling-induced hyperexcitability in the brain.
Figure 7: Increased kindling-induced spontaneous seizures in Pvalb-Cre;Erbb4−/− mice.
Figure 8: Effects of NRG1–ErbB4 signaling on kindling-induced mossy fiber sprouting.

Similar content being viewed by others

References

  1. Morimoto, K., Fahnestock, M. & Racine, R.J. Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog. Neurobiol. 73, 1–60 (2004).

    Article  CAS  Google Scholar 

  2. Hauser, W.A., Annegers, J.F. & Kurland, L.T. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34, 453–468 (1993).

    Article  CAS  Google Scholar 

  3. McNamara, J.O., Huang, Y.Z. & Leonard, A.S. Molecular signaling mechanisms underlying epileptogenesis. Sci. STKE 2006, re12 (2006).

    Article  Google Scholar 

  4. Duncan, J.S., Sander, J.W., Sisodiya, S.M. & Walker, M.C. Adult epilepsy. Lancet 367, 1087–1100 (2006).

    Article  Google Scholar 

  5. Rice, A.C. & DeLorenzo, R.J. Kindling induces long-term changes in gene expression. in. Kindling 5 (eds. Corcoran, M. & Moshe, S.) 267–284 (Plenum, 1998).

  6. Delorenzo, R.J. & Morris, T.A. Long-term modulation of gene expression in epilepsy. Neuroscientist 5, 86–99 (1999).

    Article  CAS  Google Scholar 

  7. Hughes, P.E. et al. Activity and injury-dependent expression of inducible transcription factors, growth factors and apoptosis-related genes within the central nervous system. Prog. Neurobiol. 57, 421–450 (1999).

    Article  CAS  Google Scholar 

  8. Binder, D.K., Routbort, M.J., Ryan, T.E., Yancopoulos, G.D. & McNamara, J.O. Selective inhibition of kindling development by intraventricular administration of TrkB receptor body. J. Neurosci. 19, 1424–1436 (1999).

    Article  CAS  Google Scholar 

  9. He, X.P. et al. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron 43, 31–42 (2004).

    Article  CAS  Google Scholar 

  10. Mei, L. & Xiong, W.C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452 (2008).

    Article  CAS  Google Scholar 

  11. Steiner, H., Blum, M., Kitai, S.T. & Fedi, P. Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat. Exp. Neurol. 159, 494–503 (1999).

    Article  CAS  Google Scholar 

  12. Chen, M.S. et al. Expression of multiple neuregulin transcripts in postnatal rat brains. J. Comp. Neurol. 349, 389–400 (1994).

    Article  CAS  Google Scholar 

  13. Eilam, R., Pinkas-Kramarski, R., Ratzkin, B.J., Segal, M. & Yarden, Y. Activity-dependent regulation of Neu differentiation factor neuregulin expression in rat brain. Proc. Natl. Acad. Sci. USA 95, 1888–1893 (1998).

    Article  CAS  Google Scholar 

  14. Woo, R.S. et al. Neuregulin-1 enhances depolarization-induced GABA release. Neuron 54, 599–610 (2007).

    Article  CAS  Google Scholar 

  15. Wen, L. et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Natl. Acad. Sci. USA 107, 1211–1216 (2010).

    Article  CAS  Google Scholar 

  16. Neddens, J. & Buonanno, A. Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus 20, 724–744 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Fazzari, P. et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464, 1376–1380 (2010).

    Article  CAS  Google Scholar 

  18. Fisahn, A., Neddens, J., Yan, L.Q. & Buonanno, A. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb. Cortex 19, 612–618 (2009).

    Article  Google Scholar 

  19. Vullhorst, D. et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J. Neurosci. 29, 12255–12264 (2009).

    Article  CAS  Google Scholar 

  20. McBain, C.J. & Fisahn, A. Interneurons unbound. Nat. Rev. Neurosci. 2, 11–23 (2001).

    Article  CAS  Google Scholar 

  21. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nat. Rev. Neurosci. 5, 793–807 (2004).

    Article  CAS  Google Scholar 

  22. Pitcher, G.M. et al. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med.

  23. Ting, A.K. et al. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J. Neurosci. 31, 15–25 (2011).

    Article  CAS  Google Scholar 

  24. Chen, Y.J. et al. ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation. Proc. Natl. Acad. Sci. USA.

  25. Iyengar, S.S. & Mott, D.D. Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus. Brain Res. 1208, 67–73 (2008).

    Article  CAS  Google Scholar 

  26. Ozaki, M., Itoh, K., Miyakawa, Y., Kishida, H. & Hashikawa, T. Protein processing and releases of neuregulin-1 are regulated in an activity-dependent manner. J. Neurochem. 91, 176–188 (2004).

    Article  CAS  Google Scholar 

  27. Backx, L., Ceulemans, B., Vermeesch, J.R., Devriendt, K. & Van Esch, H. Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur. J. Hum. Genet. 17, 378–382 (2009).

    Article  CAS  Google Scholar 

  28. Goddard, G.V., McIntyre, D.C. & Leech, C.K. A permanent change in brain function resulting from daily electrical stimulation. Exp. Neurol. 25, 295–330 (1969).

    Article  CAS  Google Scholar 

  29. Racine, R.J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294 (1972).

    Article  CAS  Google Scholar 

  30. Curia, G., Longo, D., Biagini, G., Jones, R.S. & Avoli, M. The pilocarpine model of temporal lobe epilepsy. J. Neurosci. Methods 172, 143–157 (2008).

    Article  CAS  Google Scholar 

  31. Roysommuti, S., Carroll, S.L. & Wyss, J.M. Neuregulin-1beta modulates in vivo entorhinal-hippocampal synaptic transmission in adult rats. Neuroscience 121, 779–785 (2003).

    Article  CAS  Google Scholar 

  32. Tidcombe, H. et al. Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc. Natl. Acad. Sci. USA 100, 8281–8286 (2003).

    Article  CAS  Google Scholar 

  33. Bjarnadottir, M. et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/− knock-outs compared with wild-type mice. J. Neurosci. 27, 4519–4529 (2007).

    Article  CAS  Google Scholar 

  34. Gu, Z., Jiang, Q., Fu, A.K., Ip, N.Y. & Yan, Z. Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J. Neurosci. 25, 4974–4984 (2005).

    Article  CAS  Google Scholar 

  35. Li, B., Woo, R.S., Mei, L. & Malinow, R. The neuregulin-1 receptor ErbB4 controls glutamatergic synapse maturation and plasticity. Neuron 54, 583–597 (2007).

    Article  CAS  Google Scholar 

  36. Chen, Q. et al. Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis. J. Neurosci. 27, 542–552 (2007).

    Article  CAS  Google Scholar 

  37. Bertram, E.H. & Cornett, J. The ontogeny of seizures in a rat model of limbic epilepsy: evidence for a kindling process in the development of chronic spontaneous seizures. Brain Res. 625, 295–300 (1993).

    Article  CAS  Google Scholar 

  38. Stoll, S.W. et al. Differential utilization and localization of ErbB receptor tyrosine kinases in skin compared to normal and malignant keratinocytes. Neoplasia 3, 339–350 (2001).

    Article  CAS  Google Scholar 

  39. Stevens, J.R. Epilepsy, psychosis and schizophrenia. Schizophr. Res. 1, 79–89 (1988).

    Article  CAS  Google Scholar 

  40. Kido, H. & Yamaguchi, N. Clinical studies of schizophrenia-like state in epileptic patients. Jpn. J. Psychiatry Neurol. 43, 433–438 (1989).

    CAS  PubMed  Google Scholar 

  41. Bruton, C.J., Stevens, J.R. & Frith, C.D. Epilepsy, psychosis, and schizophrenia: clinical and neuropathologic correlations. Neurology 44, 34–42 (1994).

    Article  CAS  Google Scholar 

  42. Sachdev, P. Schizophrenia-like psychosis and epilepsy: the status of the association. Am. J. Psychiatry 155, 325–336 (1998).

    Article  CAS  Google Scholar 

  43. Qin, P., Xu, H., Laursen, T.M., Vestergaard, M. & Mortensen, P.B. Risk for schizophrenia and schizophrenia-like psychosis among patients with epilepsy: population based cohort study. Br. Med. J. 331, 23 (2005).

    Article  Google Scholar 

  44. Bob, P., Palus, M., Susta, M. & Glaslova, K. Sensitization, epileptic-like symptoms and local synchronization in patients with paranoid schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 143–146 (2010).

    Article  Google Scholar 

  45. Cascella, N.G., Schretlen, D.J. & Sawa, A. Schizophrenia and epilepsy: is there a shared susceptibility? Neurosci. Res. 63, 227–235 (2009).

    Article  Google Scholar 

  46. García-Rivello, H. et al. Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle. Am. J. Physiol. Heart Circ. Physiol. 289, H1153–H1160 (2005).

    Article  Google Scholar 

  47. Hippenmeyer, S. et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 3, e159 (2005).

    Article  Google Scholar 

  48. Casanova, E. et al. A CamKII alpha iCre BAC allows brain-specific gene inactivation. Genesis 31, 37–42 (2001).

    Article  CAS  Google Scholar 

  49. Casanova, E. et al. ER-based double iCre fusion protein allows partial recombination in forebrain. Genesis 34, 208–214 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Gassmann (University of Basel) for kindly supplying us with heart-rescued Erbb4−/− mice, C. Lai (Indiana University) for Erbb4loxP/loxP mice, S. Arber (University of Basel) for Pvalb-cre mice and G. Schütz (German Cancer Research Center) for Camk2a-iCre and Camk2a-CreER mice. We also thank T.-M. Gao (Southern Medical University) for help concerning transgenic mice and M. Sliwkowski (Genentech) for NRG1. We are grateful to J.O. McNamara and M.-M. Poo for their comments on this work. We also thank Y.-J. Xin, X.-Y. Feng, L. Huang, B. Lu and Y. Shen for their help on genotyping, animal models and histological experiments. This work was supported in part by grants from the 973 Program (2011CBA00407), National Natural Science Foundation of China (30925016; 31021063) and Chinese Academy of Sciences (XDA01020305) to Z.Q.X. and from the US National Institutes of Health to L.M.

Author information

Author notes

  1. Guo-He Tan and Yuan-Yuan Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Guo-He Tan, Yuan-Yuan Liu, Xiao-Ling Hu & Zhi-Qi Xiong

  2. Program of Developmental Neurobiology and Department of Neurology, Institute of Molecular Medicine and Genetics, Georgia's Health Sciences University, Augusta, Georgia, USA

    Dong-Min Yin & Lin Mei

Authors
  1. Guo-He Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan-Yuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Ling Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-Min Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi-Qi Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.-H.T., Y.-Y.L. and Z.-Q.X. designed the project; G.-H.T., Y.-Y.L., X.-L.H. and D.-M.Y. performed the research; L.M. provided laboratory sources of reagents and transgenic mice. G.-H.T., Y.-Y.L., L.M. and Z.-Q.X. interpreted the data and wrote the paper.

Corresponding authors

Correspondence to Lin Mei or Zhi-Qi Xiong.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1 (PDF 3009 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, GH., Liu, YY., Hu, XL. et al. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci 15, 258–266 (2012). https://doi.org/10.1038/nn.3005

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3005

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing