Understanding neural circuits and molecular mechanisms underlying changes of synapse strength during learning and memory are the major challenges of neuroscience. However, not only learning and memory but also decay of memories is essential for proper functioning of the brain. Generally, forgetting is seen as the opposite of learning and memory. But is it really and if so how does forgetting work?

Recently, we identified musashi (msi-1), an RNA-binding protein that actively regulates forgetting in C. elegans. The role of msi-1 is stimulus-independent; deletion of the gene causes similar phenotype in different learning assays. MSI-1 is expressed in several head neurons, interacts genetically and physically with the arx1-3 mRNAs of the Arp2/3 actin branching complex and inhibits their translation. MSI-1 also regulates the persistence of GLR-1 positive synapse size increase induced by associative learning. Finally, we demonstrated that activation of GLR-1 AMPA-type glutamate receptor a) induces actin capping through the activity of adducin (add-1) and b) inhibits actin branching mediated by msi-1. These two opposite mechanisms act in concert to establish the proper memory trace. The identification of a Musashi-dependent mechanism links translational repression to regulation of the structure of the actin cytoskeleton in neurons. However many aspects of MSI-1 function remain unexplored.

In the frame of this proposal, we will investigate in depth the molecular mechanisms regulating MSI-1 activity and the MSI-1-dependent signaling pathway that induces forgetting.

1. 1. We will identify the binding partners of MSI-1 and characterize their role in the regulation of MSI-1 activity during forgetting.
2. 2. We will identify protein modifications of MSI-1 and study their role during forgetting. The identified molecules (1) and the mechanisms (2) that regulate MSI-1 will give a complex picture of the molecular mechanisms of forgetting.

Due to the functional conservation at the molecular level between C. elegans and vertebrates, our results will hopefully pave the way towards better understanding of more complex nervous systems.