Nanoscale functional analysis of mGluR5/1 in synapses – NanoMGlu

Metabotropic glutamate receptors control the physiology and the plasticity of the synapses. However, their nanoscale sub-synaptic distribution, their co-organization regarding glutamate release site determining their activation, and the relation between their activation and the signaling pathways activity is still misunderstood. Disorders like autism and mental retardation exhibit alterations in mGluR distribution, emphasizing the need for detailed investigations.
The project aims to correlate the nanoscale organization and activation of group-I mGluRs with its impact on synaptic physiology. Four main objectives will be tackled, (i) the development of tools to label and modulate the distribution of endogenous mGluR1 and 5 and to measure the downstream pathway activation. (ii) Determine the kinetics of G-protein recruitment by mGluRs. (iii) Investigate the direct relationship between nanoscale distribution of mGluRs, glutamate sources, and downstream activation of signaling pathways. (iv) Assess how mGluR localization and activation properties affect various synaptic functions, including long-term synaptic plasticity.
The NanoMGlu project aims to unravel the nanoscale organization and dynamics of post-synaptic mGluRs and their role in synaptic physiology. By combining structural-functional analysis, labeling tools development, and physiological measurements, the project addresses key questions related to mGluR activation, G-protein interaction, and downstream signaling pathways. The anticipated outcomes have implications for comprehending synaptic plasticity and may offer insights into pathologies where mGluR organization is altered, such as autism spectrum disorders.