Uncovering the role of RIN1 in coordinating AMPA-receptor membrane trafficking and structural spine changes in bidirectional synaptic plasticity

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Synaptic connections in the brain are continuously weakened or strengthened in response to specific changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is impaired in several brain disorders. Long-term potentiation (LTP) and long-term depression (LTD) are the most studied forms of activity-dependent synaptic plasticity. LTD and LTP are on one hand supported by the highly dynamic and tightly controlled trafficking and synaptic targeting of AMPA-type glutamate receptors (AMPA-Rs), which are the major mediators of fast excitatory transmission in the brain. On the other hand, dynamic remodeling of the actin cytoskeleton supports the accompanying changes in dendritic spine morphology and stability. Despite their important function in synaptic plasticity, the molecular mechanisms coordinating AMPA-R trafficking and cytoskeletal remodeling during synaptic plasticity are still not fully understood. The Ras effector protein RIN1 is highly and specifically expressed in excitatory neurons of the forebrain, particularly in the cerebral cortex, hippocampus, and amygdala. Importantly, RIN1 has a dual role as it enhances signaling of the tyrosine kinases Abl and Arg, which regulate actin cytoskeletal remodeling, and it activates the small GTPase Rab5 to facilitate receptor endocytosis. Recently, in hippocampal neurons we have found that RIN1 destabilizes synaptic connections and is a key player in postsynaptic AMPA receptor endocytosis. We further identified RIN1 to be required for activity-dependent spine plasticity during LTD. Building on our previous body of work, the overarching aim of this project is to gain comprehensive insight in how the dual functions of RIN1 orchestrate AMPA receptor trafficking and activity-dependent structural spine changes during bidirectional synaptic plasticity at excitatory synapses. Towards this end, we will combine a number of state of the art techniques including molecular manipulations of RIN1, biochemical assays, subcellular localization studies, live cell imaging experiments, and electrophysiological recordings. Biochemical studies will address the regulation of RIN1 and its protein-protein interactions. Imaging approaches will unravel plasticity-driven changes in subcellular regulation and activation of downstream signaling pathways, including their contributions to structural plasticity and AMPA-R trafficking. Finally, electrophysiological approaches will interrogate how different RIN1 functions contribute to the regulation of bidirectional synaptic strength in defined hippocampal circuits.