Different functions of fetal and adult AChR subtypes for the formation andmaintenance of neuromuscular synapses revealed in epsilon-subunit-deficient mice

Mice deficient in epsilon-subunits of the acetylcholine receptor (AChR) cha nnel die prematurely due to severe AChR deficiency that leads to the progre ssive reduction in AChR density at the neuromuscular endplate [Witzemann, V ., Schwarz, H., Koenen, M., Berberich, C., Villarroel, A., Wernig, A., Bren ner, H.R. & Sakmann, B. (1996) Proc. Natl Acad. Sci USA, 93, 13286-13291]. The mice may serve as a model for studying AChR-related myasthenic diseases . The postnatal development of the subsynaptic apparatus takes place in the absence of the adult type, epsilon-subunit-containing receptors which norm ally replace the fetal gamma-subunit-containing receptors. During later dev elopment the secondary folds of the postsynaptic membrane disappear concomi tant with the decrease in AChR density, so that the flattened-out membrane with its remaining nicotinic receptors is in close proximity to the subsyna ptic cytoplasmatic compartment and the subsynaptic myonuclei. The decrease in AChR concentration is correlated with a decrease of postsynaptic rapsyn, but has less effect on agrin, a neuronally released aggregating factor for AChRs. Thus, despite the presence of agrin at the synapse, AChR expression is not maintained at the level required to stabilize normal synaptic struc ture comprising secondary postsynaptic membrane folds. Collectively the res ults suggest that the postnatal switch from the global, activity-sensitive gamma-subunit gene transcription to the synapse-specific, activity-independ ent epsilon-subunit gene transcription is not required for the formation an d differentiation of synapses but is essential for the maintenance of the h ighly organized structure of the neuromuscular endplate.