Transforming growth factor β recruits persistent MAPK signaling to regulate long-term memory consolidation in Aplysia californica

Abstract

In this study, we explore the mechanistic relationship between growth factor signaling and kinase activity that supports the protein synthesis-dependent phase of long-term memory (LTM) consolidation for sensitization of Aplysia. Specifically, we examine LTM for tail shock-induced sensitization of the tail-elicited siphon withdrawal (T-SW) reflex, a form of memory that requires both (i) extracellular signal-regulated kinase (ERK1/2; MAPK) activity within identified sensory neurons (SNs) that mediate the T-SW and (ii) the activation of transforming growth factor b (TGFb) signaling. We now report that repeated tail shocks that induce intermediate-term (ITM) and LTM for sensitization, also induce a sustained post-training phase of MAPK activity in SNs (lasting at least 1 h). We identified two mechanistically distinct phases of post-training MAPK: (i) an immediate phase that does not require ongoing protein synthesis or TGFb signaling, and (ii) a sustained phase that requires both protein synthesis and extracellular TGFb signaling. We find that LTM consolidation requires sustained MAPK, and is disrupted by inhibitors of protein synthesis and TGFb signaling during the consolidation window. These results provide strong evidence that TGFb signaling sustains MAPK activity as an essential mechanistic step for LTM consolidation.

Autocrine signaling by anAplysianeurotrophin forms a presynaptic positive feedback loop

“…One possible answer concerns the downstream signaling pathways. ApNT, sensorin, and TGF-beta all activate Trk-like receptors that stimulate MAPK and other pathways that are critical for long-term synaptic plasticity and growth (52,54,55). It is possible that presynaptic autoreceptors are the best way to activate these signaling pathways, perhaps as a holdover from development (53).…”

ELAV proteins bind and stabilize C/EBP mRNA in the induction of long-term memory in Aplysia

“…To investigate this question, ganglia were treated with TGFb-1 (100 ng/mL, R&D Systems) starting at 45 min after Trial 1 until SN cluster collection and lysis at 1 hr after Trial 1. Treatment with TGFb-1 has previously been demonstrated to (i) recruit persistent ERK signaling, a necessary step in LTM formation, and (ii) induce long-term facilitation (LTF) in isolated Aplysia ganglia (Zhang et al, 1997;Shobe et al, 2016).…”

The Contribution of Spatial and Temporal Molecular Networks in the Induction of Long-term Memory and Its Underlying Synaptic Plasticity

“…This early phase is transient, and in the absence of additional training trials it decays to baseline by 60 minutes [37,43]. However, following repeated trial training that is permissive for the induction of LTM, MAPK is persistently activated in the SN somata 1–3 hours after training [35,42,154]. Importantly, both the early and late phases of MAPK activation are required for LTM formation [35,37].…”

“…With this minimalistic training pattern, Two-Trial training affords the unique opportunity to assay molecular and cellular changes induced by each training trial individually, as well as to explore the interaction between the molecular context established by Trial 1 and the changes induced by Trial 2. Two GF families have been reported to activate MAPK and be required for long-term plasticity in Aplysia : neurotrophins signaling via the receptor TrkB [155,156] and the TGFβ superfamily signaling via the receptor TGFβr-II [154,157–160]. Thus, as a first step in characterizing the role of different GF families during LTM formation, Kopec and colleagues [161] analyzed the necessity for TrkB and TGFβr-II signaling upstream of the early and late phases of MAPK activation induced by Two-Trial training.…”