Small G proteins exhibit pattern sensitivity in MAPK activation during the induction of memory and synaptic facilitation in Aplysia

Memory formation is highly sensitive to specific patterns of training, but the cellular and molecular mechanisms underlying pattern sensitivity are not well understood. We explored this general question by using Aplysia californica as a model system. We examined the regulation of MAPK (ERK1/2) activation by small G proteins in the CNS by using different patterns of analog stimuli that mimic different patterns of behavioral training for memory induction. We first cloned and characterized the Aplysia homologs of the small G proteins, Ras and Rap1 (ApRas and ApRap, respectively). We next examined changes in ApRas and ApRap activity that accompany MAPK activation. Last, by delivering recombinant ApRas and ApRap into the CNS, we directly manipulated their activity and examined the resultant MAPK activation. We found that MAPK activation induced by analog training depends on the combined activity of ApRas and ApRap, rather than the individual activity of either one alone. Also, ApRas and ApRap have a complex role in MAPK activation: they can act as activators or inhibitors, depending on the specific pattern of the training. The pattern-sensitive regulation of MAPK by interactive ApRas and ApRap activity that we have identified could contribute to the molecular routing of different downstream effects of spatially localized MAPK required for the induction of specific pattern-sensitive forms of synaptic facilitation and memory.