樹状突起スパイン形成におけるドレブリンの役割とAMPAおよびNMDA受容体によるドレブリン動態の二重調節

抄録

Dendritic spines represent the developmentally-regulated and activity-dependent pleomorphism based on actin cytoskeleton. However, molecular mechanisms governing the pleomorphism are unclear. First, we find that during development, synaptic drebrin clustering in dendritic filopodia is required for spine morphogenesis. Drebrin clustering with actin filaments occurs at postsynaptic sites of axon-filopodia contact. The drebrin clustering precedes and governs synaptic PSD95 clustering and spine morphogenesis. Second, using fluorescence recovery after photobleaching (FRAP) technique and immunocytochemistry, we find that activities of AMPA receptors (AMPA-Rs) and NMDA-Rs orchestrate drebrin dynamics for synaptic clustering of drebrin and PSD95. AMPA-R blockade reduces binding capacity of drebrin within spines, observed as a reduction of unrecoverable fraction. Consequently, Chronic AMPA-R blockade inhibits synaptic clustering of drebrin and PSD95. NMDA-R blockade facilitates transport of drebrin into spines, observed as a reduction of time constant. Further, chronic NMDAR blockade promotes synaptic targeting of NMDA-Rs but inhibits that of PSD95. Finally, we find that drebrin is involved in activity-dependent synaptic NMDA-R targeting. Drebrin-A knockdown inhibits the accelerated targeting of NMDA-Rs into synapses by NMDA-R blockade despite no effect on NMDA-R localization under conditions of spontaneous activities. In conclusion, activity-regulated actin-cytoskeletal system based on drebrin is critical for the diversity of spine structure. [J Physiol Sci. 2006;56 Suppl:S31]