Structural and functional alterations of neuromuscular junctions in NCAM-deficient mice.
The role of neural cell adhesion molecule (NCAM) in the development and maturation of the neuromuscular junction (NMJ) was explored by characterizing structurally and functionally NMJs from postnatal day 11 (P11) to P30 +/+, +/-, and -/- NCAM null mutant mice. Differences in NCAM levels resulted in alterations in the size and shape of NMJs, with -/- NMJs being smaller. Additionally both the withdrawal of polyneuronal innervation and the selective accumulation of synaptic vesicle protein in the presynaptic terminal were delayed. These observations suggest that the bidirectional signaling responsible for these events is impaired at -/- NMJs. Functionally, miniature end plate potential size, end plate potential size, and quantal content did not differ from that of wild type under either normal or low release conditions. However at normal release conditions, -/- NMJs, unlike +/+ NMJs, lacked paired-pulse facilitation. The most striking abnormality was the inability of NCAM null junctions to maintain transmitter output with repetitive stimuli. Combined electrophysiological and FM1-43-labeling studies suggest that NCAM null junctions are unable either to dock or to mobilize a sufficient number of vesicles at high but physiological rates of transmitter release. Taken together our observations show that many aspects of transmission are normal and, thus, that many presynaptic and postsynaptic molecules have assembled properly in the absence of NCAM. However, the fact that NCAM was required for specific aspects of transmission, including paired-pulse facilitation and reliable transmission with repetitive stimuli, suggests that NCAM either is directly involved in these processes or is required for the proper organization and/or function of other molecules underlying these processes.
Rafuse
V F
VF
Department of Neurosciences, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106-4975, USA.
Polo-Parada
L
L
Landmesser
L T
LT
D000818:Animals; D004558:Electric Stimulation; D006579:Heterozygote; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009045:Motor Endplate / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology* / Q000648:ultrastructure*; D009474:Neurons / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology
D019006:Neural Cell Adhesion Molecules