Characterization of the Memory Degradome

How memories and experiences are stored in the cellular and molecular circuitry of an organism for the duration of its lifetime is a central question in the field of neuroscience. As far back as the early fifties functional and anatomical changes of the synapse, a specialized contact between neurons, have been recognized as the epicenter of memory storage (1). Since then, a wealth of data has accumulated elucidating the mechanism of synaptic plasticity, the fluctuating strength of neuronal contacts, both in the terms of its functional efficacy as well as its physical structure. In comparison, very little effort has been applied to understanding how overt plasticity is even possible in the extracellular environment which has to be flexible enough to allow for the formation of new memories, but also rigid enough to protect already existing ones. In this proposal I explore the idea that perisynaptic proteolysis organized by a diverse set of enzymes is an arena in which these plasticity requirements can be met since tight spatial and temporal regulation of extracellular proteases provides the kind of flexibility this system needs. Although several proteases have been identified as being instrumental during memory processes, acute brain injuries or protracted neuropathologies including Alzheimer`s, Parkinson`s and Huntington`s disease, we still only have a fragmented picture of the role these critical enzymes play. Detailed in this proposal I assert that synaptic plasticity is made possible by orchestrated extracellular proteolysis, composed of temporally and spatially coupled proteases. To test this idea, I propose to survey memory-related proteolysis, identify individual components responsible for it, and validate those using genetic methods. I ultimately aim to construct a complete overview of the proteases operative during memory formation, referred to here as the memory degradome. It is well accepted that functional and structural synaptic plasticity underlies learning and memory, and understanding how it is regulated on a molecular level will bring us closer in understanding basic neuronal function and disease progression.