Differential effects of NGF and BDNF on axotomy-induced changes in GABA(A)-receptor-mediated conductance and sodium currents in cutaneous afferent neurons

The effects of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) on injury-induced changes in the electrophysiological properties of adult rat cutaneous afferent dorsal root ganglion (DRG) neurons were examined. Whole cell patch-clamp techniques were used to study gamma-aminobutyric acid-A (GABA(A))-receptor-mediated conductance, voltage-dependent sodium currents, and action potential waveform in cutaneous afferent neurons (35-60 mu m diam) cultured from control and axotomized animals. Cutaneous afferent neurons were identified by retrograde labeling with hydroxy-stilbamidine (Fluoro-gold, a fluorescent retrograde axonal tracer); the sciatic nerve was transected 1 wk after Fluoro-gold injection and L-4/L-5 DRG neurons were cultured 2-3 wk after axotomy. NGF, BDNF, or Ringer (vehicle) solution was delivered in vivo directly to the transected sciatic nerve stump in axotomized rats via an osmotic pump. Recordings were obtained from neurons 5-24 h after culture. Axotomized neurons from rats treated with vehicle solution displayed a twofold increase in GABA-induced conductance and a prominent reduction in the proportion of neurons expressing action potentials that had inflections on the falling phase. The expression of kinetically slow tetrodotoxin (TTX)-resistant sodium current was markedly reduced and an increased expression of kinetically fast TTX-sensitive current was observed in neurons from vehicle-treated, axotomized rats. Treatment with NGF (0.25 mu g/mu l at 12 mu l/day for 14 days) in axotomized animals resulted in an increase in the proportion of neurons expressing TTX-resistant, slow sodium currents and inflected action potentials, but had no effect on GABA-induced conductance. Treatment with BDNF (0.5 mu g/mu l at 12 mu l/day for 14 days) attenuated the axotomy-induced increase in GABA, receptor-mediated conductance while minimally affecting action potential waveform. The observed neurotrophin effects occurred independently of cell size changes. These findings indicate a differential regulation of GABAA receptor and sodium channel properties in axotomized rat cutaneous afferent neurons by specific neurotrophic factors.