Persistent and transcriptionally-dependent increase in protein phosphorylation in long-term facilitation of Aplysia...

From certain perspectives, short- and long-term memory seem to be a single behavioural process whose duration is a graded function of the number of training trials. Yet some clinical conditions can dissociate short- from long-term memory in human beings, and inhibitors of protein or RNA synthesis can selectively block the long-term process in experimental animals. Studies of memory for sensitization in the gill- and siphon-withdrawal reflex in Aplysia indicate that both the behavioural similarities and the differences are reflected in intrinsic cellular mechanisms in the sensory and motor neurons participating in memory storage. Although the long-term change in the synaptic connection between the sensory and motor neurons resembles a graded extension of the short-term change, its induction is selectively blocked by inhibitors of transcription or translation. We have now examined the molecular mechanisms in the sensory neurons that might account for the graded similarity between short- and long-term memory, as well as those that might contribute to the differential sensitivity to inhibitors of macromolecular synthesis. We find that a single exposure to 5-HT (a transmitter released in response to behavioural sensitizing stimuli) or cyclic AMP (a second messenger for 5-HT), which produce short-term facilitation between the sensory and motor neurons lasting minutes, leads to a short-term phosphorylation of 17 substrate proteins that is not dependent on transcription or translation. Repeated or prolonged exposure to serotonin or cAMP, which induce long-term changes in synaptic transmission lasting one or more days, induce long-term changes in phosphorylation of the same 17 proteins that are now dependent for their induction on both translation and transcription. Thus, one of the functions of the genes and proteins required for long-term facilitation may be to maintain actively in the sensory neurons an increased phosphorylation of the same set of substrate proteins involved in eliciting the physiological effects of the short-term process.