Schematic model of signaling pathways underlying long-term facilitation in Aplysia sensory neuron. The repeated treatments with neurotransmitter 5-HT activate a G-protein coupled receptor that stimulates adenylyl cyclase, which in turn activates PKA. MAPK are also activated and translocates into the nucleus. At the synaptic site, PKA stimulates the nuclear translocation of the retrograde signal molecule CAMAP via phosphorylating its Ser148. This phosphorylation results in both the dissociation from TM-apCAM and the restoration of its transcriptional activity from autoinhibition. In the nucleus, MAPK phosphorylates CREB2 which represses CREB1 and ApAF in the absence of 5-HT. Once freed from CREB2 and stimulated by PKA, CREB1 forms a homodimer to activate the downstream target gene, ApC/EBP. Translocated CAMAP acts as a co-activator of CREB1. ApC/EBP interacts with ApAF that is activated by PKA to form a core downstream effector of CREB1. ApC/EBP-ApAF heterodimer induces the late genes which are critical for the consolidation and maintenance of LTF. Robust neural activity induces and activates the transcription factor, ApLLP in the nucleus in a calcium-dependent manner. ApLLP induces ApC/EBP expression and lowers the threshold for LTF induction. Elucidating the downstream molecule of ApC/EBP remains to be challenged. SNS, strong noxious stimulus.