Pattern detection in the TGFβ cascade controls the induction of long-term synaptic plasticity

Transforming growth factor β (TGFβ) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFβ inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFβ acts as a "repetition detector"during the induction of two-trial LTM. Secretion of the biologically inert TGFβ proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/ Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFβ in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFβ cascade that together are necessary for the induction of long-lasting memories.