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English

Organization of Presynaptic Active Zones In Neuromuscular Junctions

【Date】  2012.9.25.(Tue)16:00-17:30

【Place】  3rd floor Seminar room, Nanobiol. Bldg.

【Speaker】 Dr. Hiroshi Nishimune (西宗裕史)
      (University of Kansas Medical School, Department of Anatomy and Cell Biology)

- Organization of Presynaptic Active Zones In Neuromuscular Junctions -

【Abstract】
Presynaptic active zones play essential roles for the function and pathology of neuromuscular junctions (NMJs) because they are synaptic vesicle release sites. We recently reported that the number of active zones increases as the size of mouse NMJs increases 3-fold during postnatal development, however, the density of active zones remains constant from postnatal day 0 to 54. What is the molecular mechanism for organizing active zones? Recent findings in the central and peripheral nervous systems demonstrate that synaptic channel proteins are involved in the formation and maintenance of synapses by interacting directly with synapse organizers. We identified that presynaptic voltage-dependent calcium channels (VDCC) of NMJs interact extracellularly with the muscle-derived synapse organizer laminin β2 and intracellularly with active zone proteins, Bassoon, CAST/Erc2, and ELKS. These results suggest that VDCCs function as a scaffolding protein to organize the active zones. Consistent with this model, double knockout mice for P/Q- and N-type VDCCs has a significantly reduced number of active zones at NMJs and features an attenuation of the active-zone proteins. These molecular mechanisms of active zone organization and the loss of active zones in VDCC knock out mice are consistent with the pathological conditions observed in Lambert-Eaton myasthenic syndrome cause by autoantibodies against VDCCs and Pierson syndrome caused by laminin β2 mutation. Interestingly, the active zone density decreases at the NMJs of aged mice. These results suggest that NMJs maintain the density of synaptic vesicle release sites while they mature, but this density becomes impaired during aging. Importantly, decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The exercise increased Bassoon immunoreactivity in NMJs without affecting the synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with active zone protein Bassoon.

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