Neurotrophic control of channel properties at neuromuscular synapses of rat muscle.

1. Ectopic neuromuscular synapses formed when the fibular nerve was implanted into the proximal part of rat soleus muscle and the soleus nerve was cut. The gating properties of acetylcholine (ACh) receptor channels in the newly formed ectopic and in the denervated original end-plates were examined at various stages of ectopic synapse formation.2. At ectopic end-plates the apparent mean open time of ACh receptor channels changes during synaptic development. Channels in immature ectopic end-plates, examined 1 week after cutting the soleus nerve, have apparent mean open times of approximately 4 ms (at -70 mV, 22 degrees C), similar to those of the extrasynaptic ACh receptor channels of completely denervated fibres. The channel gating of mature ectopic end-plates, examined 3-7 weeks after nerve section, is characterized by a mean open time of approximately 1 ms and resembles that found in normal end-plates of adult fibres.3. The conversion of end-plate channel gating occurs during the second and third week of synapse formation. During this period two discrete classes of channels with different gating behaviour are present in the ectopic end-plate.4. Examination of ectopic end-plates in the electron microscope reveals that junctional folds begin to appear in the subsynaptic membrane during the period of channel conversion.5. At the denervated original end-plates of ectopically innervated fibres the apparent mean open time of ACh receptor channels remains similar to that of normally innervated end-plates. Original end-plates retain the normal synaptic class of channel for at least 42 days after denervation. At this time, most of the ACh receptors present originally in the membrane have been replaced by newly inserted receptors.6. At former end-plates of completely denervated fibres ACh activates two classes of channels, even when most of the ACh receptors originally present in the end-plate have been replaced by new receptors.7. The results show that during synapse formation a neurally controlled conversion of ACh receptor channels occurs about 2-3 weeks after establishment of the nerve muscle contact. Thereafter end-plate channel properties are independent of neural influences. These observations are consistent with a mechanism of channel conversion whereby the nerve modifies not the ACh receptor channel itself, but another constituent of the end-plate membrane which determines the gating properties of end-plate channels.