Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats

Authors

  • Jeffrey C. Petruska,

    1. Department of Neurobiology and Behavior, SUNY-Stony Brook, Stony Brook, NY 11794, USA
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    • Present address: Department of Anatomical Sciences and Neurobiology, Department of Neurological Surgery, Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY 40292, USA.

  • Brandon Kitay,

    1. The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Vanessa S. Boyce,

    1. Department of Neurobiology and Behavior, SUNY-Stony Brook, Stony Brook, NY 11794, USA
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  • Brian K. Kaspar,

    1. Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA
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    • Present address: Nationwide Children’s Research Institute, Columbus, OH; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.

  • Damien D. Pearse,

    1. The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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  • Fred H. Gage,

    1. Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA
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  • Lorne M. Mendell

    1. Department of Neurobiology and Behavior, SUNY-Stony Brook, Stony Brook, NY 11794, USA
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Lorne M. Mendell
E-mail: lorne.mendell@sunysb.edu

Abstract

We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed, indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long-lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury.

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