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

28 Citations (Scopus)

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
Pages (from-to)997-1005
Number of pages9
JournalEuropean Journal of Neuroscience
Volume32
Issue number6
DOIs
StatePublished - Sep 1 2010

Fingerprint

Neurotrophin 3
Dependovirus
Motor Neurons
Synaptic Transmission
Excitatory Postsynaptic Potentials
Spinal Ganglia
Spinal Cord
Muscle Spindles
Injections
Tropism
Spinal Nerve Roots
Nerve Growth Factors
Reference Values
Skeletal Muscle

Keywords

  • electrophysiology
  • gene therapy
  • spinal cord
  • viral vector

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats. / Petruska, Jeffrey C.; Kitay, Brandon; Boyce, Vanessa S.; Kaspar, Brian K.; Pearse, Damien D; Gage, Fred H.; Mendell, Lorne M.

In: European Journal of Neuroscience, Vol. 32, No. 6, 01.09.2010, p. 997-1005.

Research output: Contribution to journalArticle

Petruska, Jeffrey C. ; Kitay, Brandon ; Boyce, Vanessa S. ; Kaspar, Brian K. ; Pearse, Damien D ; Gage, Fred H. ; Mendell, Lorne M. / Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats. In: European Journal of Neuroscience. 2010 ; Vol. 32, No. 6. pp. 997-1005.
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