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ERC

VERTICAL CITY Report Summary

Project ID: 646788
Funded under: H2020-EU.1.1.

Periodic Reporting for period 1 - VERTICAL CITY (Versatility of scaffold complexes in vivo to control synaptic plasticity)

Reporting period: 2015-06-01 to 2016-11-30

Summary of the context and overall objectives of the project

Memory is a dynamic process. At all time we have to encode new information and recall old ones. Brain plasticity is thought to be the basis of memory encoding. Each of our sensorial or emotional experience will indeed transform our brain. There is no specific area where memories are stored. Memory is spread all over the brain. This spreading comes from the biological processes that sustain the encoding and storage of new information. When stimulated by new information, a neuron will make contact (synapse) with other nervous cells. The more it is solicited, the more new synapses it will form with other neurons, as numerous mnesic traces speared in brain areas defined by the nature of stimuli. Thus, specific connections between neurons and neuronal communication efficiency control the encoding of information and its storage. The efficiency of synaptic transmission is controlled at synapses by the release of a chemical messenger (neurotransmitter) by the activated neuron, and the activation of a receptor’s neurotransmitter on the connected neuron. Receptors and associated scaffolds, together called receptosome, are relatively stable structures, but indeed exchange of individual adaptor proteins can occur on a short time scale and in a highly regulated manner, which provides fine-tuning, speed, and specificity to the receptor signaling. Therefore, understanding how receptor function is affected by the composition and dynamics of complexes is an essential biological concern that will offer the opportunity to target exclusively the therapeutically relevant signaling pathway of a given receptor. We propose that in the brain, receptosome dynamics is involved in fine-tuning synaptic transmission and plasticity, which might be crucial for cognitive functions.
We are establishing the link between molecular events, neuronal signaling and memory performance. More than correlations, this project proposes live recording of molecular events and cellular signaling during memory encoding. These technologies will enable to monitor the versatility of protein-protein interactions in space and time ranging from in cellulo to in vivo BRET imaging in freely behaving animals. To conclude, we will establish the functional significance of oligomer remodeling in the physiological synaptic plasticity and try to restore it in neurological disorders.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have already engineered and validated tools to follow, prevent or repair interactions between proteins at synapses. We improved a high-sensitivity microscope-based technology to study protein dynamics in living cells, in real time. This work has been recently published in Scientific Reports (1). We also broaden the applications of BRET by monitoring simultaneously 3 interactors at the same time (2). We started to study the function of protein dynamics at synapses and their defects in a mouse model of mental retardation in cellulo (3). We constructed a microscope ended by a thin fiberscope that will be implanted in a mouse brain, in order to record neuronal signaling in freely behaving mice before, during and after specific cognitive trainings. We are now developing a viral strategy to express tagged proteins into the mouse brain to record protein interactions in vivo.
In parallel, we identified genes which expression is modified in a mouse model of mental retardation, compared to WT mice. This lists of genes will be soon published to be available for the scientific community.

1. Goyet E, Bouquier N, Ollendorff V, Perroy J. Fast and high resolution single-cell BRET imaging. Scientific reports. 2016;6:28231.
2. Pradhan AA, Perroy J, Walwyn WM, Smith ML, Vicente-Sanchez A, Segura L, et al. Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta Opioid Receptor Function. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2016;36(12):3541-51.
3. Guo W, Ceolin L, Collins KA, Perroy J, Huber KM. Elevated CaMKIIalpha and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model. Cell reports. 2015;13(10):2297-311.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

First, this proposal is groundbreaking because it will make the link between molecular events, neuronal signaling and memory performance. More then correlations, this project proposes live recording of molecular events and cellular signaling during memory encoding. Second, new specific therapeutic targets will be proposed to treat mental deficiencies: By opposition to pharmaceutical compound interfering with the ligand-biding pocket of the receptor, we here propose to play on scaffold interactions. This strategy will only modify a specific altered function of glutamate receptor without modifying other functions of the receptor (thus, avoiding undesired side effects). Third, within the scope of this proposal innovative powerful tools / technics will be developed that will be of high interest for the broad community of researchers in life sciences to highlight the versatility of protein-protein interactions in space and time ranging from in cellulo to in vivo BRET imaging in freely behaving animals.
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