Different patterns of electrical activity lead to long-term potentiation by activating different intracellular pathways.

Deciphering and storing information coded in different firing patterns are important properties of neuronal networks, as they allow organisms to respond and adapt to external and internal events. Here we report that hippocampal CA1 pyramidal neurons respond to brief bursts of high-frequency stimulation (HFS) and θ burst stimulation (TBS) with long-lasting enhanced responses (long-term potentiation [LTP]), albeit by engaging different signaling pathways. TBS induces LTP through calpain-1-mediated suprachiasmatic nucleus circadian oscillatory protein degradation, ERK activation, and actin polymerization, whereas HFS requires adenosine A2 receptors, PKA, and actin polymerization. TBS- but not HFS-induced LTP is impaired in calpain-1 knock-out mice. However, TBS-induced LTP and learning impairment in knock-out mice are restored by activating the HFS pathway. Thus, different patterns of rhythmic activities trigger potentiation by activating different pathways, and cross talks between these can be used to restore LTP and learning when elements of the pathways are impaired.