Neurotrophins have been implicated in activity-dependent synaptic plasticity, but the underlying intracellular mechanisms remain Largely unknown. Synaptic potentiation induced by brain-derived neurotrophic factor (BDNF), but not neurotrophin 3, was prevented by blockers of adenosine 3＇,5＇-monophosphate (cAMP) signaling. Activators of cAMP signaling alone were ineffective in modifying synaptic efficacy but greatly enhanced the potentiation effect of BDNF. Blocking cAMP signaling abolished the facilitation of BDNF-induced potentiation by presynaptic activity. Thus synaptic actions of BDNF are gated by cAMP. Activity and other coincident signals that modulate cAMP concentrations may specify the action of secreted neurotrophins on developing nerve terminals.