Local neurotrophic repression of gene transcripts encoding fetal AChRs at rat neuromuscular synapses

Abstract

The spatio-temporal expression patterns of mRNA transcripts coding for acetylcholine receptor (AChR) subunits and myogenic factors were measured in denervated rat soleus muscle and in soleus muscle chronically paralyzed for up to 12 d by conduction block of the sciatic nerve by tetrodotoxin (TTX). In denervated muscle the AChR α-, β-, γ-, and δ-subunit mRNAs were elevated with highest expression levels in the former synaptic and the perisynaptic region and with lower levels in the extrasynaptic fiber segments. In muscle paralyzed by nerve conduction block the α-, β-, γ-, and δ-subunit mRNA levels increased only in extra-synaptic fiber segments. Surprisingly, in the synaptic region the γ-subunit mRNA that specifies the fetal-type AChR, and α-, β-, δ-subunit mRNAs were not elevated. The expression of the gene encoding the ε-subunit, which specifies the adult-type AChR, was always restricted to synaptic nuclei. The mRNA for the regulatory factor myogenin showed after denervation similar changes as the subunit transcripts of the fetal AChR. When the muscle was paralyzed by nerve conduction block the increase of myogenin transcripts was also less pronounced in synaptic regions compared to extrasynaptic fiber segments. The results suggest that in normal soleus muscle a neurotrophic signal from the nerve locally down-regulates the expression of fetal-type AChR channel in the synaptic and perisynaptic muscle membrane by inhibiting the expression of the γ-subunit gene and that inhibition of the myogenin gene expression may contribute to this down- regulation.