CRCNS: US-French Research Proposal: Synaptic plasticity rules under physiological conditions for hippocampus and cerebellum

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One of the central hypotheses of neuroscience is that memories are stored in the brain through modifications of synaptic connectivity. This synaptic plasticity has been studied extensively in vitro, and these experiments have led to the formalization of mathematical rules that describe how specific patterns of pre- and post-synaptic activity lead to changes in synaptic strength. However, the vast majority of these experimental studies have been performed in conditions that are far from physiological. In particular, calcium is known to be critical for the induction of synaptic plasticity in many preparations, but the extracellular calcium concentration used in most studies is significantly higher than the experimentally measured concentration in vivo.The goal of the present collaborative project is to understand the rules of synaptic plasticity under physiological conditions in two major brain structures, the hippocampus and the cerebellum. It groups together a theoretical team (Brunel) with expertise in synaptic plasticity models, and two experimental teams with expertise in hippocampal plasticity (Debanne) and cerebellar plasticity (Barbour). The theoretical team has recently discovered that in a calcium-based model of synaptic plasticity, lowering the extracellular calcium concentration drastically changes the standard plasticity rules that have been widely assumed. Preliminary experiments performed by both the Debanne and Barbour teams have confirmed that plasticity is reduced, or even completely abolished, in protocols that induce plasticity at higher calcium levels. This project will investigate further plasticity rules under conditions that are far closer to in vivo conditions than traditional in vitro studies, through a tight collaboration among the three labs. In particular, the collaborators will investigate whether neuromodulation and/or realistic patterns of activity can rescue plasticity that they found to be absent at physiological calcium levels. They aim to produce minimal biophysical models of synaptic plasticity that will fit the recorded data, and explain how plasticity is determined by a few key biophysical variables: extracellular calcium concentration, nitric oxide, and neuromodulators. Such a mathematical description of plasticity rules under physiological conditions will serve both the theoretical community, by enabling efficient simulation and analytical calculation, and experimental research, by offering insight into key mechanisms of plasticity.This project will contribute to scientific exchanges between the US and France. Joint workshops will be held in both countries and their participants will contribute to a tutorial-based Masters course combining theoretical and experimental study of research problems in neuroscience. A companion project is being funded by the French National Research Agency (ANR).