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Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain

Nature Medicine volume 12, pages 677–681 (2006)Cite this article

Abstract

Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain1,2. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses3,4,5, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor–dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.

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Figure 1: Nociceptive activity–induced changes in spinal expression of Homer1 variants in a model of unilateral hindpaw inflammation.
Figure 2: Calcium imaging using Fura-2 on acute spinal slices derived from rats expressing EGFP or EGFP-tagged Homer1a via gene delivery mediated by SFV or AAV virions to the spinal dorsal horn in vivo.
Figure 3: Effects of Homer1a expression on spine density and activation of ERK1/2 in the spinal cord.
Figure 4: Effects of spinal expression of AAV-Homer1a, AAV-Homer1c (both tagged with hemagglutinin epitope) or EGFP (control) on nocifensive behavior associated with inflammatory pain in mice in vivo.

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Acknowledgements

The authors are grateful to P.F. Worley for the gift of rat Homer1a and Homer1c cDNAs; P.H. Seeburg for the gift of a plasmid containing the Homer1a 3′ UTR; M. Schaefer, B. Heinke and O. Friedrich for help with calcium imaging experiments; and to T. Kuner and S. Offermanns for critically reading an earlier version of this manuscript. This work was supported by an Emmy Noether-program fellowship from the Deutsches Forschunggemeinschaft to R.K.

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Author notes

  1. Matthias Klugmann and Ceng Luo: These authors contributed equally to this work.

Authors and Affiliations

  1. Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany

    Anke Tappe, Ceng Luo, David Hirlinger, Nitin Agarwal & Rohini Kuner

  2. Department of Molecular Medicine & Pathology, University of Auckland, 85 Park Road, Auckland, New Zealand

    Matthias Klugmann & Matthew J During

  3. Department of Anesthesiology and General Intensive Care, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria

    Justus Benrath

  4. Brain Research Institute, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland

    Markus U Ehrengruber

  5. Institute for Neurobiology, IZN, University of Heidelberg, Im Neuenheimer Feld 364, Heidelberg, 69120, Germany

    Matthias Klugmann, Markus U Ehrengruber & Matthew J During

  6. Kantonsschule Hohe Promenade, Promenadengasse 11, Zürich, CH-8001, Switzerland

    Matthias Klugmann, Markus U Ehrengruber & Matthew J During

  7. Department of Neurological Surgery, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Matthias Klugmann, Markus U Ehrengruber & Matthew J During

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  1. Anke Tappe
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Corresponding author

Correspondence to Rohini Kuner.

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Supplementary information

Supplementary Fig. 1

Specificity controls for antibodies to Homer1 variants and mRNA expression in rat dorsal root ganglia. (PDF 137 kb)

Supplementary Fig. 2

Demonstration of spinal knockdown of Homer1a using AAV virions expressing shRNA targeted against Homer1a and EGFP bicistronically. (PDF 167 kb)

Supplementary Fig. 3

Analysis of mice injected with AAV1/2 virions expressing Homer1a, Homer1c, EGFP, Homer1a shRNA or control shRNA in the superficial spinal parenchyma for basal nociceptive sensitivity and motor performance. (PDF 25 kb)

Supplementary Fig. 4

Analysis of calcium responses in spinal neurons expressing Homer1 or EGFP via either SFV or AAV virions in dissociated cultures or spinal slices. (PDF 184 kb)

Supplementary Table 1

Comparison of relative levels of expression of Homer proteins induced by nociceptive activity or by AAV-mediated expression in spinal dorsal horn. (PDF 19 kb)

Supplementary Methods (PDF 79 kb)

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Tappe, A., Klugmann, M., Luo, C. et al. Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain. Nat Med 12, 677–681 (2006). https://doi.org/10.1038/nm1406

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