Drebrin is a major F-actin binding protein in the brain. We have recently demonstrated that the expression of drebrin A (neuron specific isoform) is rapidly upregulated in parallel with synapse formation, and that it governs the targeting of postsynaptic density (PSD) protein PSD-95 to synapses. Immunoelectron microscopy demonstrated that drebrin A is first appeared at the submembranous regions of developing excitatory postsynaptic sites at the initial stage ofsynapse formation. To determine the role of drebrin A on excitatory synapse formation, we analyzed whether the suppression of drebrin A expression affects filopodia-spine morphology and synaptic targeting of NMDA receptors in cultured hippocampal neurons. Suppression of developmentally programmed upregulation of drebrin A by antisense treatment significantly decreased the density and width of filopodia-spines. Immunocytochemistry showed that the antisense treatment did not attenuate synaptic clustering of NMDA receptors under condition that permitted spontaneous activities, but inhibited the accelerated targeting of NMDA receptors into synapses by its antagonist AP5. These results indicate that drebrin A upregulation play a pivotal role in spine morphogenesis and activity-dependent synaptic targeting of NMDA receptors. [J Physiol Sci. 2006;56 Suppl:S23]