Dendritic spines are the major sites of excitatory synaptic transmission, and their morphogenesis plays a pivotal role in neuronal development and plasticity. Recent studies suggest the correlation between spine morphology and spine functions. Diversity in synapse functions is related to the diversity in spine morphology. As one of the candidate which control spine morphology, we focused on a major actin-binding protein in the brain, drebrin A (DA). We hypothesized that spine morphology depends on DA, and we analyzed spine ultrastructure in terms of DA localization using immunoelectron microscopy. We have recently reported that only 75% of spines are DA immuno-positive in adult rat cortex. We first analyzed if there was any morphological differences between DA immuno-positive spine (DPS) and DA immuno-negative spines (DNS). We found that DPS were larger in the spine head area and in the post synaptic density (PSD) length. Next, we analyzed if overexpression of DA changed spine morphology, using DA transgenic mice (Tg) that overexpressed DA in the forebrain. Similar to wild type mice (WT), DPS were larger than DNS in Tg; however, spine head area of DPS was significantly smaller than that of WT. The amount of DA within each spine did not change between two genotypes. These data suggest that overexpression of DA leads to smaller DPS with higher concentration of DA. There were no differences between two genotypes in the ratio of DPS to DNS, the spine density, and the DA localization within spines. These results indicate that DA is involved in spine morphology in vivo although its molecular mechanism is not yet clarified. [J Physiol Sci. 2006;56 Suppl:S83]