Investigating the relationship between posttranslational modifications and neuronal activity in controling AMPA receptor expression

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It is evident that the mammalian brain plays a central role in various tasks such as memory formation and learning. In order to do so, the brain relies on its ability to preserve the function of specific neuronal connections called synapses. Given that synapses are the functional units of the brain where specific neurotransmitter receptors are localized, understanding the specific mechanisms that accurately and precisely regulate their function is of prime importance. The abundance of AMPA-type glutamate receptors (AMPAR) at hippocampal synapses determines synaptic efficacy and is thus crucial for learning and memory. In this context, there is a critical need for fundamental research aimed at elucidating physiological molecular mechanisms regulating AMPAR synaptic expression. Recent evidences including my prior work show that AMPARs are modified through phosphorylation, ubiquitination and other posttranslational modifications that control channel conductance, receptor trafficking and synaptic expression. Over the years, AMPAR phosphorylation has been described as critical regulator of intracellular routing and synaptic plasticity. Besides, the ubiquitin system preserves cell homeostasis by acting as the primary mechanism of protein quality control, and specifically regulates AMPARs trafficking and expression. Despite evidences that support a relationship between the ubiquitination and the phosphorylation of AMPARs, the exact mechanism underlying such an intricate interplay remains an open question that requires attention. In this context, the goal of my proposal is to shed light on how neuronal activity and the relationship between phosphorylation and ubiquitination are interrelated for controlling the abundance of AMPARs at hippocampal synapses.By means of molecular, biochemical and cellular methods, my 5-years research plan aims to unravel the functional interplay between ubiquitination and phosphorylation for the regulation of AMPAR at hippocampal synapses. Specifically, my proposed research will address the following aims: Aim 1. Identify the enzymes that modify the phosphorylation of AMPAR as an underlying mechanism to control subunit ubiquitination. Aim 2. Define how the phosphorylation of specific residues modulates AMPAR ubiquitination. Aim 3. Determine how AMPAR phosphorylation and ubiquitination regulate synaptic scaling. At the completion of this proposal, I anticipate that our research activities will elucidate a dynamic mechanism controlling the synaptic expression of AMPARs. Our work will have a significant impact in fundamental sciences because it has the potential to transform our vision of the mechanisms involved in synaptic plasticity. Our work will undeniably contribute to the advancement of knowledge regarding the molecular mechanisms controlling hippocampal excitatory neurotransmission.