EFFECTS OF 4-AMINOPYRIDINE ON MUSCLE AND MOTOR UNIT FORCE IN CANINE MOTOR-NEURON DISEASE

Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an autosomal domi nant disorder of motor neurons that shares features with human motor n euron disease. In animals exhibiting the accelerated phenotype (homozy gotes), we demonstrated previously that many motor units exhibit funct ional deficits that likely reflect underlying deficits in neurotransmi ssion. The drug 4-aminopyridine (4AP) blocks voltage-dependent potassi um conductances and is capable of increasing neurotransmission by over coming axonal conduction block or by increasing transmitter release. I n this study, we determined whether and to what extent 4AP could enhan ce muscle force production in HCSMA. Systemic 4AP (1-2 mg/kg) increase d nerve-evoked whole muscle twitch force and electromyograms (EMG) to a greater extent in older homozygous animals than in similarly aged, s ymptomless HCSMA animals or in one younger homozygous animal. The poss ibility that this difference was caused by the presence of failing mot or units in the muscles from homozygotes was tested directly by admini stering 4AP while recording force produced by failing motor units. The results showed that the twitch force and EMG of failing motor units c ould be significantly increased by 4AP, whereas no effect was observed in a nonfailing motor unit from a symptomless, aged-matched HCSMA ani mal. The ability of 4AP to increase force in failing units may be rela ted to the extent of failure. Although 4AP increased peak forces durin g unit tetanic activation, tetanic force failure was not eliminated. T hese results demonstrate that the force outputs of failing motor units in HCSMA homozygotes can be increased by 4AP. Possible sites of 4AP a ction are considered.