PLASTINHIB · Molecular Plasticity of Inhibitory Synapses

Neurons maintain a precise organization of their membrane into sub-domains with specific molecular compositions, together with the capacity to change it in response to plasticity events. However, as seen with the tracking of single molecules, receptors in the plasma membrane continuously exchange between synaptic and extrasynaptic locations. Interactions between neurotransmitter receptors and postsynaptic scaffold proteins control the distribution of receptors at synaptic and extrasynaptic sites. This mechanism is modulated at many levels, and contributes to the regulation of the synaptic strength of excitatory and inhibitory synapses in physiological and pathological conditions. This project will address the gap in knowledge between the molecular instability of randomly diffusing receptors and the stable functional architecture of synapses. It will provide new insights into fundamental issues related to the cellular basis of neuronal information processing. Focusing on inhibitory Glycine and GABAA receptors (GlyR, GABAAR) I will have 3 main objectives:Objective 1: to determine key aspects of the relationship between the synapse microstructure, molecular dynamics, and molecular interactions.Objective 2: characterize the mechanisms by which receptor diffusion contributes to the adaptation of inhibitory synapses to excitatory activity.Objective 3: understand how non-neuronal glial cells modulate inhibitory receptor diffusion-trapping and ultimately impact on neuronal excitability.For this research, single molecule methods and super-resolution microscopy give access to molecular dynamics (tracking), the morphology at high resolution, and quantitative data such as dwell times and absolute numbers of molecules, thus identifying new cellular mechanisms accounting for the regulation of inhibitory synaptic strength.