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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Decoding Synaptic Memory with TimeSTAMP

Alternative title: null

Awarded: NOK 6.0 mill.

The project examines brain mechanism of memory formation at the level of neuronal communication at the synapse. Changes in synaptic strength are key to information storage in neuronal circuits, underlying process of memory formation, with relevance to cognitive flexibility. The plasticity of synapse is disturbed in Alzheimer's disease and other neuropsychiatric disorders. This project sets out to identify the mechanisms regulating synthesis and function of the Arc protein. The study has uncovered a novel form of protein synthesis regulation crucial for long-lasting changes in synaptic communication. The process occurs in two distinct mechanistic phases. In the first phase, proteins controlled by fragile-x mental retardation protein are synthesis, in the second phase a global increase in protein synthesis occurs. The work so far is important in uncovering what amounts to a "program"for changing neural circuits at the synaptic level in the adult brain. Progress was also make in identify regulator control on the Arc protein itself. The addition of SUMO protein to Arc is coupled interaction of the protein with actin cytoskeleton and function in strengthening synaptic connections (long-term potentiation). Arc function is also modulated by phosphorylation. ERK mediated phosphorylation regulates localization of Arc, while GSK mediated phosphorylation regulates degradation of the Arc. The work represents a significant step toward understanding elucidating the molecular control of Arc protein, as a highly specialized master organizer of synaptic plasticity and cognition.

The vertebrate-specific gene, Arc, is now widely recognized as a master regulator of synaptic plasticity, cortical development, and memory formation. Uniquely, Arc mRNA is rapidly transported from the cell body into dendritic branches where the local synt hesis of Arc protein underlies both long-term potentiation (LTP) and depression (LTD) of synaptic connectivity. Elucidation of this remarkable bidirectional control of synaptic function by newly synthesized Arc is fundamentally important for understanding higher brain function and dysfunction. We will address this key question by combining electrophysiological and imaging studies with the application of novel drug-controlled tags (TimeSTAMP) to biochemically isolate new Arc proteins and track their synthe sis in real time. Importantly, these strategies will be integrated with the biochemical identification of Arc protein-protein interaction complexes specific to LTP or LTD. Furthermore, we hypothesize that post-translational modification of Arc by SUMOylat ion toggles Arc function between LTP and LTD, by switching its protein-protein interactions. The aims are to identify sites of Arc synthesis and trafficking during LTP and LTP, time-dependent protein partnerships formed by Arc, and the role of SUMOylatio n in directing Arc trafficking and coupling to LTP and LTD-specific effector proteins. In sum, this project aims to reveal the biological logic of synaptic memory as mediated by Arc.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering