Drebrin A, one of the most abundant neuron-specific F-actin-binding proteins, is found exclusively in dendrites and is particularly concentrated in dendritic spines receiving excitatory inputs. We investigated the role of drebrin A in synaptic transmission and found that overexpression of drebrin A augmented the glutamatergic synaptic transmission, probably through an increase of active synaptic site density. Interestingly, overexpression of drebrin A also affected the frequency, amplitude and kinetics of miniature inhibitory postsynaptic currents (mIPSCs), despite the fact that GABAergic synapse density and transmission efficacy were not modified. Downregulation of drebrin A led to a decrease of both glutamatergic and GABAergic synaptic activity. In heterologous cells, drebrin A reorganized and stabilized F-actin and these effects were mediated by its actin-binding domain. Thus, drebrin A might regulate dendritic spine morphology via regulation of actin cytoskeleton remodeling and dynamics. Our data demonstrate for the first time that drebrin A modulates glutamatergic and GABAergic synaptic activities.