Investigation of the molecular mechanisms of synaptic tagging and capture

Memory formation is continuously influenced by past, present, and future experiences. Memories linked to events that require more attention or involve emotional arousal are more persistent than ordinary memories. Information from multiple inputs that consist of memory is integrated in the hippocampus, a brain region responsible for memory storage. As a form of hippocampal long-term potentiation, pathway-specific synaptic tagging and capture (STC) has been proposed as a synaptic model of memory because it illustrates the interaction of two independent sets of synapses. This pathway-specificity is a remarkable property of neuronal signaling because it requires highly coordinated cellular signaling only at the activated synapses. However, elucidating the mechanism that is responsible for this specificity is a big challenge in the field. In my dissertation, I focused on PKA anchoring and RNA-binding proteins because they can contribute to STC through compartmentalization of PKA signaling and regulation of dendritic expression of RNAs, respectively. In Chapter 1, I review the mechanism of STC and discuss how compartmentalized PKA signaling contributes to STC. PKA is involved in the process of STC by orchestrating the activity of synaptic molecules and by mediating gene expression. In Chapter 2, I combine genetic and pharmacological approaches to determine the role of PKA anchoring in STC and memory. The results from electrophysiological, biochemical and behavioral experiments suggest that presynaptically anchored PKA contributes to STC and memory by regulating the size of the readily releasable pool of synaptic vesicles. In Chapter 3, I perform genetic and viral approaches to define whether an RNA-binding protein translin (also known as testes-brain RNA-binding protein, TBRBP) is involved in STC and memory. The data from electrophysiological, behavioral and gene expression studies suggest that translin mediates STC and memory via RNA processing. Taken together, my thesis work provides evidence that presynaptic PKA anchoring-mediated synaptic vesicle release and postsynaptic processing of specific RNAs by translin are critical for STC and memory