Neuromuscular transmission and muscle contractility in SNAP-25-deficient coloboma mice.
Synaptosomal associated protein of 25 kDa (SNAP-25) is a cytoplasmic protein that participates in the docking and fusion of synaptic vesicles with the nerve terminal in preparation for neurotransmitter release. SNAP-25 is also a substrate for three of the seven serotypes of botulinum neurotoxin (BoNT). Intoxication by BoNT/A, /C1 or /E results in weakness and paralysis of skeletal muscle due to cleavage of SNAP-25 (and syntaxin la in the case /C1) at discrete serotype-specific sites. To elucidate the role of SNAP-25 in muscle function in more detail, contractility and neuromuscular transmission were studied in a mutant mouse model termed coloboma. The coloboma mutation results from a contiguous deletion of 1-2 centiMorgans on chromosome 2, which includes the entire SNAP-25 locus and three other identified genes. Homozygotes do not survive beyond gestation day 6; heterozygotes (Cm/+) have a normal life-span but express reduced levels of SNAP-25 mRNA and protein in the brain. The consequences of the Cm/+ mutation on twitch and tetanic tension, quantal release of neurotransmitter and spinal motoneuron expression of SNAP-25 were examined in the present study. Contrary to expectations, Cm/+ mice exhibited no alteration in twitch tension and generated normal tetanic tension even at the highest frequency examined (800 Hz). Microelectrode recordings revealed that MEPP amplitude and frequency were both within control limits. The ventral spinal cord of Cm/+ mice showed no deficiency in SNAP-25 content and immunohistochemical examination of nerve terminals in Cm/+ mice disclosed that SNAP-25 levels and distribution were similar to those of control mice. It is concluded that spinal motor neurons up-regulate SNAP-25 to preserve vital neuromuscular function.
Adler
M
M
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. michael.adler@amedd.army.mil
Sheridan
R E
RE
Deshpande
S S
SS
Oyler
G A
GA
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001905:Botulinum Toxins / Q000633:toxicity; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D003964:Diaphragm / Q000294:innervation / Q000502:physiology; D004558:Electric Stimulation; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D009045:Motor Endplate / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009469:Neuromuscular Junction / Q000235:genetics* / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25
D000631:Aminopyridines; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; C038615:2,3-diaminopyridine; D001905:Botulinum Toxins