Volado, the gene encoding the Drosophila alphaPS3-integrin, is required for normal short-term memory formation (Grotewiel et al., 1998), supporting a role for integrins in synaptic modulation mechanisms. We show that the Volado protein (VOL) is localized to central and peripheral larval Drosophila synapses. VOL is strongly concentrated in a subpopulation of synaptic boutons in the CNS neuropil and to a variable subset of synaptic boutons at neuromuscular junctions (NMJs). Mutant morphological and functional synaptic phenotypes were analyzed at the NMJ. Volado mutant synaptic arbors are structurally enlarged, suggesting VOL negatively regulates developmental synaptic sprouting and growth. Mutant NMJs exhibit abnormally large evoked synaptic currents and reduced Ca(2+) dependence of transmission. Strikingly, multiple forms of Ca(2+)- and activity-dependent synaptic plasticity are reduced or absent. Conditional Volado expression in mutant larvae largely rescues normal transmission and plasticity. Pharmacologicially disrupting integrin function at normal NMJs phenocopies features of mutant transmission and plasticity within 30-60 min, demonstrating that integrins acutely regulate functional transmission. Our results provide direct evidence that Volado regulates functional synaptic plasticity processes and support recent findings implicating integrins in rapid changes in synaptic efficacy and in memory formation.