Local regulation of the levels and activity of synaptic proteins is critical to plasticity. In this proposal, we investigate the role of translation in regulation of the levels of CaMKII and characterize the functional roles of the interaction of Eag and dCASK with CaMKII. The genetic tools available in Drosophila allow us to apply the results of our biochemical studies to the design of novel strategies for understanding behavior.
Specific Aim #1. Translational control of CaMKII and plasticity. New synthesis of CaMKII is important for long-term memory, and much of the new synthesis is localized to synaptic regions. The mechanisms by which localization and regulated synthesis occurs are just beginning to be elucidated and both the rasi/siRISC pathway (flies) and CPEBP pathway (rodents and our preliminary results) have been implicated. In this aim we will determine what processes regulate CaMKII synthesis and how they relate to behavior.
Specific Aim #2. Non-channel role of Eag in plasticity. Eag is a voltage-gated potassium channel, but in Drosophila, mutants in this channel affect multiple currents. We have identified an alternative product of the Eag locus that is produced in response to activation of multiple signal transduction pathways and encodes a non-channel protein with potential for nuclear signaling. We will determine if this protein functions directly at synapses and/or whether it regulates gene expression.
Specific Aim #3. Behavioral effects of dCASK regulation of CaMKII autophosphorylation. dCASK regulates the autophosphorylation of CaMKII. By increasing T306 phosphorylation (which blocks CaM binding) when synaptic activity is low, this protein can downregulate the activatable pool of CaMKII at synapses that are inactive. T306 phosphorylation also has an impact on subsequent phosphorylation of T287, the 'memory'site on CaMKII: blocking switching into the active state. dCASK is therefore a 'gain controller'for both the calcium-dependent and calcium-independent activities of CaMKII. In this aim we will use dCASK to modulate the levels of CaMKII autophosphorylation in vivo and assess learning and memory formation. These studies will provide insight into local and genetic regulation of synaptic processes. Understanding these processes is fundamental to understanding behavior.
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