Processing of TGFbeta as a mechanism for precise temporal orchestration in long term memory formation

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PROJECT SUMMARY One of the great challenges of modern neuroscience is understanding the detailed molecular choreography required for the formation of lasting memories in the brain. At the heart of this challenge lies a complex network of molecular processes that must be integrated at precise timepoints to create a cellular environment favorable for long-term memory (LTM) formation. However, the neurobiological processes and the precise timing of their signaling cascades during LTM formation remain to be fully understood. One family of molecular processes that could contribute to the temporal requirements for LTM formation is growth factor (GF) signaling. GFs, canonically viewed as regulators of developmental plasticity, are becoming widely appreciated as key mediators of synaptic plasticity and memory in adults. Recent findings from our laboratory show that a specific GF, transforming growth factor beta (TGFβ), provides a unique mechanism that plays a major role in the temporal processing underlying LTM. This project will test the novel hypothesis that TGFβ’s signaling cascade can act as a “molecular timekeeper” through the integration of its activity, contributing to the temporal computations necessary for LTM formation. To this end, I will examine three distinct components of the TGFβ signaling cascade during LTM: (i) TGFβ-ligands, (ii) TGFβ-receptors, and (iii) downstream mediator proteins, to determine how each component uniquely contributes to the temporal processing necessary for LTM formation. In Aim I, I will examine how synthesis and/or release of TGFβ-ligands could each be key events whose timing is necessary for LTM formation. In Aim II, I will study how TGFβ ligand activation, through proteolysis and changes at the level of TGFβ-receptors, may be critical time-keeping events. Finally, in Aim III, I will assess whether TGFβ-initiated intracellular singling via Smad proteins is necessary for LTM formation. For all experiments, I will use a powerful paradigm developed to study LTM in the marine mollusk Aplysia. This paradigm induces LTM for sensitization after only two trials, but only if the trials are separated by a specific, highly constrained time window of 45 minutes. This minimal system separates the initiating stimulus (Trial 1) from the repeated stimulus (Trial 2), providing unparalleled access to the specific temporal interactions underlying LTM formation. Finally, this project has the potential to contribute significant impact from a clinical perspective, as these findings will have direct implications for understanding human memory formation under healthy conditions and when compromised in neurological disease. Since TGFβ’s signaling cascade has been implicated in the pathogenesis of many of these neurological disorders, understanding when and how TGFβ acts in the brain during memory formation could provide novel avenues for developing more effective and targeted therapeutics.