Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats.
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.
Petruska
Jeffrey C
JC
Department of Neurobiology and Behavior, SUNY-Stony Brook, Stony Brook, NY 11794, USA.
Kitay
Brandon
B
Boyce
Vanessa S
VS
Kaspar
Brian K
BK
Pearse
Damien D
DD
Gage
Fred H
FH
Mendell
Lorne M
LM
D000367:Age Factors; D000818:Animals; D002460:Cell Line; D000229:Dependovirus / Q000502:physiology*; D016503:Drug Delivery Systems / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007273:Injections, Intramuscular; D009046:Motor Neurons / Q000502:physiology*; D020933:Neurotrophin 3 / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology*
D020933:Neurotrophin 3