Intramuscular AAV delivery of NT‐3 alters synaptic transmission to motoneurons in adult rats |
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| Authors: | Jeffrey C. Petruska Brandon Kitay Vanessa S. Boyce Brian K. Kaspar Damien D. Pearse Fred H. Gage Lorne M. Mendell |
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| Affiliation: | 1. Department of Neurobiology and Behavior, SUNY‐Stony Brook, Stony Brook, NY 11794, USA;2. 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.;3. The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA;4. Laboratory of Genetics, The Salk Institute, La Jolla, CA, USA;5. Present address: Nationwide Children’s Research Institute, Columbus, OH;6. Department of Pediatrics, The Ohio State University, Columbus, OH, USA. |
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| 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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| Keywords: | electrophysiology gene therapy spinal cord viral vector |
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