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. AAVBDNF was significantly more effective than AAVNT-3 in eliciting locomotion. In fact, AAVBDNF-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 AAVNT-3 or AAVGFP were incapable of hindlimb stepping during this task, despite provision of balance support. AAVNT-3 treatment did promote the recovery of treadmill-assisted stepping, but this required continuous perineal stimulation. In addition, AAVBDNF-treated rats were sensitized to noxious heat, whereas AAVNT-3-treated and AAVGFP-treated rats were not. Notably, AAVBDNF-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 AAVBDNF significantly reduced motoneuron rheobase, suggesting that AAVBDNF 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 AAVBDNF treatment indicated increased activation of interneurons in the vicinity of the locomotor central pattern generator. AAVNT-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.