DEVELOPMENT OF ELECTRICAL MYOTONIA IN THE ADR MOUSE - ROLE OF CHLORIDE CONDUCTANCE IN MYOTUBES AND NEONATAL ANIMALS

In the ADR mouse, the homozygous condition of the autosomal mutation adr, ''arrested development of righting response'', leads to the symptoms of myotonia. The adr mutation is caused by an insertion of a retroposon into a gene for a chloride channel (adr = Clc-1) that is expressed in adults, but only at very low levels in neonate rodent muscle. In the present study, we investigated the earliest stages of the ADR myotonia. In muscle from 7-day-old ADR mice that can be recognized by inspection, electrical after-activities are distinct by their low frequency (1-5 Hz) and long duration (several minutes) from those recorded in adult muscle. Similar myotonic symptoms could be evoked in muscle fibres from 7 day wildtype mice after substitution of the external chloride with impermeant anions or by activators of protein kinase C. The genotypes of 3-day-old mice cannot be inferred from inspection and, thus, were identified by Southern blotting with a ClC-1 probe. Although no +/+ animal showed characteristic myotonic series, these were seen both in adr/adr and in most adr/+ animals. Thus, due to the low dosage of chloride channels in 3-day-old mouse muscle, the adr mutation appears to be partially dominant rather than fully recessive, as in adult mice. No indication of electrical myotonia could be demonstrated in cultured myotubes, although their pattern of excitability depended on the presence of external chloride ions. We conclude that the low Cl--conductance of myotubes influences excitability but is not controlled by the adr/Clc-1 gene. In contrast, in the neonate mouse normal excitability depends on a normal dosage of functional Clc-1 alleles.