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Reversible Unilateral Nigrostriatal Pathway Inhibition Induced Through Expression of Adenovirus-mediated Clostridial Light Chain Gene in the Substantia Nigra

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Abstract

Clostridial light chain (LC) inhibits synaptic transmission by digesting a vesicle-docking protein, synaptobrevin, without killing neurons. We here report the feasibility of creating a rat hemiparkinsonism model through LC gene expression in the substantia nigra (SN), inhibiting nigrostriatal transmission. 40 adult Sprague Dawley rats were divided into four groups for SN injections of PBS, 6-hydroxydopamine (6-OHDA), or adenoviral vectors for the expression of LC (AdLC), or GFP (AdGFP). Amphetamine and apomorphine induced rotations were assessed before and after SN injection, revealing significant rotational alterations at 8 or 10 days after injection in both AdLC and 6-OHDA but not PBS and AdGFP groups. Induced rotation recovered by one month in AdLC rats but persisted in 6-OHDA rats. Histological analysis of the SN revealed LC and GFP expression with corresponding synaptobrevin depletion in the LC, but not the GFP groups. Tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry (IHC) showed markedly decreased staining in ipsilateral SN and striatum in 6-OHDA but not AdLC or AdGFP rats. Similarly, compared with contralateral, ipsilateral striatal dopamine level only decreased in 6-OHDA but not AdLC, AdGFP, or PBS treated rats. Thus, LC expression induces nigral synaptobrevin depletion with resulting inhibition of nigrostriatal synaptic transmission. Unlike 6-OHDA, LC expression inhibits synaptic activity without killing neurons. This approach, therefore, represents a potentially reversible means of nigrostriatal pathway inhibition as a model for Parkinson’s disease. Such a model might facilitate transient and controlled nigral inhibition for studying striatal recovery, dopaminergic re-innervation, and normalization of striatal receptors following the recovery of nigrostriatal transmission.

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Acknowledgment

This research was supported by the grant from NINDS KO8 NS43305.

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Authors and Affiliations

  1. Departments of Neuroscience and Neurosurgery, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Jun Yang, Qingshan Teng, Mary E. Garrity-Moses, Shearwood McClelland III, Thais Federici, Erin Carlton, Jonathon Riley & Nicholas M. Boulis

  2. Department of Neuroscience and Center for Neurological Restoration, Cleveland Clinic, Lerner Research Institute, NB 2-126, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Nicholas M. Boulis

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  1. Jun Yang
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  2. Qingshan Teng
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  3. Mary E. Garrity-Moses
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  8. Nicholas M. Boulis
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Correspondence to Nicholas M. Boulis.

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Yang, J., Teng, Q., Garrity-Moses, M.E. et al. Reversible Unilateral Nigrostriatal Pathway Inhibition Induced Through Expression of Adenovirus-mediated Clostridial Light Chain Gene in the Substantia Nigra. Neuromol Med 9, 276–284 (2007). https://doi.org/10.1007/s12017-007-8003-0

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  • DOI: https://doi.org/10.1007/s12017-007-8003-0

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