Translational Switch for Long Term Maintenance of Synaptic Plasticity

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By Harel Shouval, TMC.

Synaptic plasticity, the experience dependent change in synaptic efficacies, provides a physiological basis of learning and memory storage (Bear, 1996; Morris et al., 2000). Theoretical considerations requires that synaptic plasticity must be synapse specific if it is to provide sufficient neuronal selectivity, but must also be long lasting if it is indeed the basis of long lasting learning and memory. However, synapses are composed of proteins which turnover at rates that are much faster than memory lifetimes. Therefore, there must be a synapse specific biological mechanism to preserve synaptic efficacies in face of protein turnover.
Long term potentiation (LTP), a long lasting cellular manifestation of synaptic plasticity, can be divided into two forms: Early phase LTP (E-LTP) is induced by a ‘weak’ stimulus, is protein synthesis independent, and last for 2-4 hours, whereas late phase LTP (L-LTP) which requires a ‘strong’ stimulus lasts much longer and depends on the synthesis of new proteins (Frey et al., 1988; Kang and Schuman, 1996). Although both transcription and translation have been implicated in L-LTP, we concentrate here on the effect of translation, because nuclear transcription cannot account for synapse specificity.
A popular theory is that the maintenance of long-term memory and synaptic plasticity is accomplished through a bi-stable molecular switch. Specifically, most attention has been given to theory that autophosphorylation of αCaMKII can form a bistable switch that is resistant to phosphatases and protein turnover (Lisman and Goldring, 1988; Lisman and Zhabotinsky, 2001; Miller, 2005; Zhabotinsky, 2000). This theory is challenged by several theoretical and experimental findings, which I will describe.
The main objective of this work is to explore a possible link between activity dependent temporal and spatial regulation of gene expression and lifelong stability of some memories despite the rapid turnover of their molecular substrates. In this talk I will describe work that examines the hypothesis that a molecular loop between a kinase and a translation regulation factor acts as a bistable switch to stabilize activity induced synaptic plasticity over long periods of time. I will specifically describe one such loop which involves positive feedback between CaMKII and CPEB a molecule that regulates the translation of CaMKII. I will show that this loop can be bistable and can account for the differential effects of protein synthesis inhibitors during the induction and maintenance phases of L-LTP.
During this presentation I will also discuss the methodology used for modeling molecular processes. I will display the problem with the mass action approach used here, discuss viable alternatives, their advantages and disadvantages.

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