The Vesl-1S/Homer-1a protein is induced during long-term potentiation (LTP), and contains a motif that binds postsynaptic proteins. We have previously reported that synaptic accumulation of Vesl-1S/Homer-1a immunoreactivity (IR) at synapses on the contour of neuronal somata is promoted by stimulation of cells with phorbol esters, 90 mM KCl or proteasome inhibitors. In the present study, we investigated the intracellular mechanism that results in the synaptic accumulation of this protein at synapses. MEK inhibitors completely blocked the effects of phorbol esters and KCl on the accumulation of Vesl-1S/Homer-1a and partially blocked the effect of proteasome inhibitors. Conversely, brain-derived neurotrophic factor (BDNF) and NT3 promoted the accumulation of Vesl-1S/Homer-1a IR at synapses. The extent of this accumulation is correlated with the level of activation of extracellular signal-regulated kinases, ERK following treatment with BDNF. BDNF also caused an increase in the amount of Vesl-1S/Homer-1a protein, but this occurred after Vesl-1S/Homer-1a had accumulated at the synapses. In addition, inhibition of de novo protein synthesis did not affect the phorbol ester-mediated accumulation of Vesl-1S/Homer-1a IR at synapses. These results indicate that activation of the ERK cascade plays a crucial role in the synaptic accumulation of Vesl-1S/Homer-1a IR, and suggest that this accumulation occurs mainly by re-localization of Vesl-1S/Homer-1a protein, and not through an increase in the level of Vesl-1S/Homer-1a. Activity-dependent release of neurotrophins or depolarization may cause local activation of the ERK cascade to produce the synapse-specific localization of Vesl-1S/Homer-1a.