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Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination

Gene Therapy volume 12, pages 108–119 (2005)Cite this article

A Corrigendum to this article was published on 06 January 2005

Abstract

Clostridial neurotoxins have assumed increasing importance in clinical application. The toxin's light chain component (LC) inhibits synaptic transmission by digesting vesicle-docking proteins without directly altering neuronal health. To study the properties of LC gene expression in the nervous system, an adenoviral vector containing the LC of tetanus toxin (AdLC) was constructed. LC expressed in differentiated neuronal PC12 cells was shown to induce time- and concentration-dependent digestion of mouse brain synaptobrevin in vitro as compared to control transgene products. LC gene expression in the rat lumbar spinal cord disrupted hindlimb sensorimotor function in comparison to control vectors as measured by the Basso–Beattie–Bresnahan (BBB) scale (P<0.001) and rotarod assay (P<0.003). Evoked electromyography (EMG) showed increased stimulus threshold and decreased response current amplitude in LC gene-transferred rats. At the peak of functional impairment, neither neuronal TUNEL staining nor reduced motor neuron density could be detected. Spontaneous functional recovery was observed to parallel the cessation of LC gene expression. These results suggest that light chain gene delivery within the nervous system may provide a nondestructive means for focused neural inhibition to treat a variety of disorders related to excessive synaptic activity, and prove useful for the study of neural circuitry.

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Acknowledgements

We thank Thomas Binz, PhD of the Medizinische Hochschule, Hannover, Germany for providing anti-LC antibodies and Sean Sweeney, PhD of the University of California, San Francisco for providing plasmid DNA. We also thank Dr Michael Imperiale of the University of Michigan for providing the adenovirus vector. This work was supported by the National Institutes of Health KO8 Grant NS43305, the Amyotrophic Lateral Sclerosis Association, and the Christopher Reeves Paralysis Foundation.

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Authors and Affiliations

  1. Department of Neuroscience, Lerner Research Institute, Cleveland, OH, USA

    Q Teng, D K Tanase, J K Liu, M E Garrity-Moses & K B Baker

  2. Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA

    N M Boulis

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  1. Q Teng
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Teng, Q., Tanase, D., Liu, J. et al. Adenoviral clostridial light chain gene-based synaptic inhibition through neuronal synaptobrevin elimination. Gene Ther 12, 108–119 (2005). https://doi.org/10.1038/sj.gt.3302400

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