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Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition

Molecular Psychiatry volume 17, pages 99–107 (2012)Cite this article

Abstract

Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to an essential role of phosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneuron dendrite length occurs in schizophrenia, understanding how NRG1-erbB4 signaling modulates interneuron dendritic morphogenesis might shed light on disease-related alterations in cortical circuits.

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References

  1. Kalus P, Bondzio J, Federspiel A, Muller TJ, Zuschratter W . Cell-type specific alterations of cortical interneurons in schizophrenic patients. NeuroReport 2002; 13: 713–717.

    Article  PubMed  Google Scholar 

  2. Akbarian S, Huang HS . Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev 2006; 52: 293–304.

    Article  CAS  PubMed  Google Scholar 

  3. Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev 2005; 6: 312–324.

    Article  CAS  Google Scholar 

  4. Lewis DA, Gonzalez-Burgos G . Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 2008; 33: 141–165.

    Article  PubMed  Google Scholar 

  5. Lee WC, Huang H, Feng G, Sanes JR, Brown EN, So PT et al. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol 2006; 4: e29.

    Article  PubMed  Google Scholar 

  6. Corfas G, Roy K, Buxbaum JD . Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci 2004; 7: 575–580.

    Article  CAS  PubMed  Google Scholar 

  7. Mei L, Xiong WC . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev 2008; 9: 437–452.

    Article  CAS  Google Scholar 

  8. Harrison PJ, Law AJ . Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry 2006; 60: 132–140.

    Article  CAS  PubMed  Google Scholar 

  9. Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci 2009; 29: 12255–12264.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Fazzari P, Paternain AV, Valiente M, Pla R, Lujan R, Lloyd K et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 2010; 464: 1376–1380.

    Article  CAS  PubMed  Google Scholar 

  11. Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci USA 2010; 107: 1211–1216.

    Article  CAS  PubMed  Google Scholar 

  12. Gerecke KM, Wyss JM, Carroll SL . Neuregulin-1beta induces neurite extension and arborization in cultured hippocampal neurons. Mol Cell Neurosci 2004; 27: 379–393.

    Article  CAS  PubMed  Google Scholar 

  13. Krivosheya D, Tapia L, Levinson JN, Huang K, Kang Y, Hines R et al. ErbB4-neuregulin signaling modulates synapse development and dendritic arborization through distinct mechanisms. J Biol Chem 2008; 283: 32944–32956.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Li B, Woo RS, Mei L, Malinow R . The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron 2007; 54: 583–597.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K et al. Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci USA 2009; 106: 4507–4512.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Ma XM, Huang J, Wang Y, Eipper BA, Mains RE . Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines. J Neurosci 2003; 23: 10593–10603.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Xie Z, Srivastava DP, Photowala H, Kai L, Cahill ME, Woolfrey KM et al. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron 2007; 56: 640–656.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Penzes P, Johnson RC, Sattler R, Zhang X, Huganir RL, Kambampati V et al. The neuronal Rho-GEF kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis. Neuron 2001; 29: 229–242.

    Article  CAS  PubMed  Google Scholar 

  19. Kushima I, Nakamura Y, Aleksic B, Ikeda M, Ito Y, Shiino T et al. Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia Susceptibility. Schizophr Bull 2010 (in press).

  20. Hill JJ, Hashimoto T, Lewis DA . Molecular mechanisms contributing to dendritic spine alterations in the prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2006; 11: 557–566.

    Article  CAS  PubMed  Google Scholar 

  21. Narayan S, Tang B, Head SR, Gilmartin TJ, Sutcliffe JG, Dean B et al. Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res 2008; 1239: 235–248.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T . Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001; 411: 494–498.

    Article  CAS  PubMed  Google Scholar 

  23. Kojima S, Vignjevic D, Borisy GG . Improved silencing vector co-expressing GFP and small hairpin RNA. BioTechniques 2004; 36: 74–79.

    Article  CAS  PubMed  Google Scholar 

  24. Helmstaedter M, Sakmann B, Feldmeyer D . L2/3 interneuron groups defined by multiparameter analysis of axonal projection, dendritic geometry, and electrical excitability. Cereb Cortex 2009; 19: 951–962.

    Article  PubMed  Google Scholar 

  25. Xie Z, Cahill ME, Penzes P . Kalirin loss results in cortical morphological alterations. Mol Cell Neurosci 2010; 43: 81–89.

    Article  CAS  PubMed  Google Scholar 

  26. Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S et al. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron 2005; 45: 525–538.

    Article  CAS  PubMed  Google Scholar 

  27. Ma XM, Wang Y, Ferraro F, Mains RE, Eipper BA . Kalirin-7 is an essential component of both shaft and spine excitatory synapses in hippocampal interneurons. J Neurosci 2008; 28: 711–724.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Penzes P, Cahill ME, Jones KA, Srivastava DP . Convergent CaMK and RacGEF signals control dendritic structure and function. Trends Cell Biol 2008; 18: 405–413.

    Article  CAS  PubMed  Google Scholar 

  29. Chakrabarti K, Lin R, Schiller NI, Wang Y, Koubi D, Fan YX et al. Critical role for kalirin in nerve growth factor signaling through TrkA. Mol Cell Biol 2005; 25: 5106–5118.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H 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 2007; 27: 4519–4529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hanke JH, Gardner JP, Dow RL, Changelian PS, Brissette WH, Weringer EJ et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. J Biol Chem 1996; 271: 695–701.

    Article  CAS  PubMed  Google Scholar 

  32. Rio C, Buxbaum JD, Peschon JJ, Corfas G . Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4. J Biol Chem 2000; 275: 10379–10387.

    CAS  PubMed  Google Scholar 

  33. Vecchi M, Carpenter G . Constitutive proteolysis of the ErbB-4 receptor tyrosine kinase by a unique, sequential mechanism. J Cell Biol 1997; 139: 995–1003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R . The involvement of ErbB4 with schizophrenia: association and expression studies. Am J Med Genet B 2006; 141B: 142–148.

    Article  CAS  Google Scholar 

  35. Penzes P, Jones KA . Dendritic spine dynamics—a key role for kalirin-7. Trends Neurosci 2008; 31: 419–427.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Hayashi-Takagi A, Takaki M, Graziane N, Seshadri S, Murdoch H, Dunlop AJ et al. Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci 2010; 13: 327–332.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Gerlai R, Pisacane P, Erickson S . Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav Brain Res 2000; 109: 219–227.

    Article  CAS  PubMed  Google Scholar 

  38. Cahill ME, Xie Z, Day M, Photowala H, Barbolina MV, Miller CA et al. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proc Natl Acad Sci USA 2009; 106: 13058–13063.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from NIH-NIMH (R01MH071316), National Alliance for Research on Schizophrenia and Depression (NARSAD) to PP, NIH (MH078833) to UM, Ruth L Kirschstein National Research Service Awards 1F31AG031621-01A2 to MEC and 1F31MH085362 to KAJ, Christopher Reeve Foundation to CSB. All experiments involving animals were carried out according to the Institutional Animal Care and Use Committee of Northwestern University.

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Authors and Affiliations

  1. Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    M E Cahill, K A Jones, I Rafalovich, Z Xie & P Penzes

  2. Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA

    C S Barros & U Müller

  3. School of Biological Sciences, Bangor University, Bangor, UK

    C S Barros

  4. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    P Penzes

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  1. M E Cahill
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Correspondence to P Penzes.

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Cahill, M., Jones, K., Rafalovich, I. et al. Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. Mol Psychiatry 17, 99–107 (2012). https://doi.org/10.1038/mp.2011.35

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