Differential effects of brain-derived neurotrophic factor and neurotrophin-3 on hindlimb function in paraplegic rats.
We compared the effect of viral administration of brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (NT-3) on locomotor recovery in adult rats with complete thoracic (T10) spinal cord transection injuries, in order to determine the effect of chronic neurotrophin expression on spinal plasticity. At the time of injury, BDNF, NT-3 or green fluorescent protein (GFP) (control) was delivered to the lesion via adeno-associated virus (AAV) constructs. AAV-BDNF was significantly more effective than AAV-NT-3 in eliciting locomotion. In fact, AAV-BDNF-treated rats displayed plantar, weight-supported hindlimb stepping on a stationary platform, that is, without the assistance of a moving treadmill and without step training. Rats receiving AAV-NT-3 or AAV-GFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAV-NT-3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAV-BDNF-treated rats were sensitized to noxious heat, whereas AAV-NT-3-treated and AAV-GFP-treated rats were not. Notably, AAV-BDNF-treated rats also developed hindlimb spasticity, detracting from its potential clinical applicability via the current viral delivery method. Intracellular recording from triceps surae motoneurons revealed that AAV-BDNF significantly reduced motoneuron rheobase, suggesting that AAV-BDNF promoted the recovery of over-ground stepping by enhancing neuronal excitability. Elevated nuclear c-Fos expression in interneurons located in the L2 intermediate zone after AAV-BDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAV-NT-3 treatment reduced motoneuron excitability, with little change in c-Fos expression. These results support the potential for BDNF delivery at the lesion site to reorganize locomotor circuits.
Department of Neurobiology and Behavior, Life Sciences Building, Room 532, State University of New York at Stony Brook, Stony Brook, NY 11794-5230, USA.
Vanessa S
VS
Boyce
Jihye
J
Park
Fred H
FH
Gage
Lorne M
LM
Mendell
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D004195:Disease Models, Animal; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006614:Hindlimb; D006801:Humans; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D020933:Neurotrophin 3 / Q000008:administration & dosage* / Q000235:genetics; D010264:Paraplegia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3