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Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors

Nature Medicine volume 16, pages 694–700 (2010)Cite this article

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Abstract

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.

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Figure 1: Constitutive 5-HT2 receptor activity, but not residual 5-HT, causes spasms.
Figure 2: Constitutive 5-HT2 receptor activity contributes to LLRs in the isolated spinal cord in vitro.
Figure 3: Constitutively active 5-HT2 receptors on motoneurons contribute to Ca2+ PICs underlying spasms.
Figure 4: A highly constitutively active 5-HT2C receptor isoform is upregulated with injury.
Figure 5: 5-HT2 receptor inverse agonist blocks spasms in spinal cord injured humans.
Figure 6: Spontaneous recovery of locomotion in staggered-hemisected rats depends on constitutively active 5-HT2 receptors.

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Acknowledgements

Thanks to F. Geddes, T. Tanaka, K. Miyake, G. Van Patten, J. Nevett-Duchcherer, G. Funk, M. Finlay and L. Hahn for assistance. This research was supported by the Alberta Heritage Foundation, Canadian Institutes of Health Research and the US National Institutes of Health (NS47567 and NS48170).

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Author notes

  1. David J Bennett and Karim Fouad: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Neuroscience, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada

    Katherine C Murray, Marilee J Stephens, Michelle Rank, Philip J Harvey, Xiaole Li, R Luke W Harris, Edward W Ballou, Romana Vavrek, Leo Sanelli, David J Bennett & Karim Fouad

  2. Department of Anesthesiology & Intensive Care, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan

    Aya Nakae & Takashi Mashimo

  3. Centre for Neuroscience, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Jessica D'Amico, Roberta Anelli & Monica A Gorassini

  4. Department of Physiology, Northwestern University, Chicago, Illinois, USA

    Charles J Heckman

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Contributions

K.C.M. performed the in vitro rat experiments, contributed to all other rat studies and co-wrote the paper. M.R., P.J.H., R.L., W.H., L.S., M.J.S., R.V., X.L. and K.F. contributed to the in vivo rat experiments. K.F., R.V., E.W.B., R.A. and C.J.H. contributed to immunolabeling experiments. K.F. co-wrote the paper and shared equally with D.J.B. in senior authorship (last author). A.N. and T.M. conducted mRNA analysis. J.D. and M.A.G. conducted the human experiments. D.J.B. performed in vitro and in vivo rat experiments, supervised or co-supervised all of the experiments and co-wrote the paper.

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Correspondence to David J Bennett.

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The authors declare no competing financial interests.

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Murray, K., Nakae, A., Stephens, M. et al. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med 16, 694–700 (2010). https://doi.org/10.1038/nm.2160

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