The transcription factor CREB is critical for several forms of experience-dependent plasticity in a range of species and is commonly activated in neurons by calcium/calmodulin-dependent protein kinase IV (CaMKIV). Surprisingly, little is known about the neural circuit adaptations caused by activation of CaMKIV and CREB. Here, we use viral-mediated gene transfer in vivo to examine the consequences of acute expression of constitutively active forms of CaMKIV and CREB on synaptic function in the rodent hippocampus. Acute expression of active CaMKIV or CREB caused an enhancement of both NMDA receptor-mediated synaptic responses and long-term potentiation (LTP). This was accompanied by electrophysiological and morphological changes consistent with the generation of "silent synapses," which provide an ideal substrate for further experience-dependent modifications of neural circuitry and which may also be important for the consolidation of long-term synaptic plasticity and memories.