The Right Time for a Synapse to Change: Windows and Mechanisms of Multiday Training Trials

Although learning over multiple days is more effective than a single day of training, the underlying cellular mechanisms of repeated training trials remain poorly understood. With a combination of empirical and computational approaches, we determined a critical time window for a second stimulus block of a multiday training protocol to augment long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse and long-term enhancement of neuronal excitability (LTEE), two cellular correlates of learning and memory. A second stimulus block delivered 24 h after the first block significantly enhanced LTF and LTEE, but was without effect at 18 or 32 h. This spacing effect appears due, at least in part, to the dynamics of competition between the transcription activator cAMP response element-binding protein 1 (CREB1) and repressor CREB2. The timer mechanism is intrinsic to individual neurons, as LTEE exhibited this critical temporal window in isolated sensory neurons. These findings suggest the dynamics of transcription factors function as a cellular timer that establishes a window of eligibility for a second learning trial to enhance memory.