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

Jeffrey C. Petruska, Brandon Kitay, Vanessa S. Boyce, Brian K. Kaspar, Damien D. Pearse, Fred H. Gage, Lorne M. Mendell

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)997-1005
Number of pages9
JournalEuropean Journal of Neuroscience
Volume32
Issue number6
DOIs
StatePublished - Sep 2010

Keywords

  • electrophysiology
  • gene therapy
  • spinal cord
  • viral vector

ASJC Scopus subject areas

  • Neuroscience(all)

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