Molecular control of Arc protein: Decoding a master regulator of synaptic plasticity and cognition

The ability to remember, to store and retrieve information in the brain, is vital to everyday life. Lasting changes in neuronal connectivity typical require new protein synthesis. This Top Research project focuses on the role of a protein known as Arc. Arc is considered to be a master regulator of plasticity, required for both strengthening and weakening of connections. However, little is known about how the protein works and how it is regulated. The goal of this project is to elucidate the molecular structure, function, and regulation of the Arc protein. In the course of this project we have identified binding partners of Arc involved in regulation of the neuronal cell cytoskeleton (drebrin) and binding to the endoplasmic reticulum (calnexin), and how localization of Arc in the neuron is controlled. Information obtained on the molecular structure of Arc protein and its domains has further shed light the molecular function of Arc, both with regarding to Arc signaling and formation of virus-like capsids. Evidence suggest that Arc binding to protein partners at synapses regulates the abundance neurotransmitter receptors. Moreover, the toppforsk team has elucidated a key mechanism for the self-association of Arc leading to the formation of virus-like capsids.

The toppforsk project has ushered in a new era of investigation on the structure-function of Arc. It is now possible to study Arc at the level of its domains for the first time. This provides numerous opportunities for interrogating the molecular function of Arc for basic research on plasticity, memory and cognition, and for translational research on dysregulation of plasticity in brain disorders. Looking forward, the field faces an intriguing dichotomy, as Arc is both a signaling hub and capable of forming virus-like capsid shell capable of transmitting RNA between cells. The results from toppforsk have elucidated Arc functions and established methods and rationale approaches for dissecting Arc modalities. Through Toppforsk we have created a valuable collaborative platform which we hope to further develop in years ahead.

A major goal of neuroscience is to elucidate the molecular control of synaptic plasticity, as a cellular basis for adaptive changes in neural circuits of importance for memory, cognition, and numerous brain disorders. New gene transcription and protein synthesis are essential for persistent synaptic change in both long-term potentiation (LTP) and depression (LTD). However, changes in synaptic strength are enacted at the level of individual proteins and protein interaction networks. This is the level that must be targeted in order to decipher, and gain control of, long-term synaptic plasticity. Convergent lines of evidence have identified the immediate early protein, Arc, as a master regulator of LTP, LTD, and long-term memory. Hence, a major outstanding challenge is to elucidate how the Arc protein is controlled at the molecular level, and how Arc function is switched or toggled between LTP and LTD. A breakthrough is made possible by our pioneering work, including the first paper on the biophysical and structural properties of the Arc protein. Here, we present a bold proposal to interrogate the master role of Arc and its protein interaction network in synaptic plasticity. In two interlocking specific aims, we will determine the role of Arc phosphorylation and oligomerization in dictating LTP and LTD formation by controlling Arc substrate binding and cellular effector pathways. Our approach combines molecular neuroscience, neurophysiology, and fluorescent protein imaging with protein structural biology, biochemistry and biophysics. Novel optical tools will be developed for imaging Arc activity-states and for reversibly blocking Arc function. In addition, we aim to discover small molecular weight compounds that regulate Arc oligomeric state and function. We foresee a paradigm shift in the which we explain how long-term synaptic plasticity shapes cognition and identify molecular targets for treatment of brain disorders in which the Arc complex has been implicated.