A New Trans-Synaptic Bridge: Functional characterization of the NMDA receptor-Neurexin-2 interaction

Overview

Project Summary

Proper neuronal communication depends on the receptor's precise localization on the postsynaptic side and the presynaptic release of neurotransmitters. To achieve this architecture, cell adhesion molecules play a major role in the establishment of transsynaptic connections. This proposed innovative project aims to study the interaction between two major synaptic players, the GluN2B subunit of NMDA receptors (NMDAR) and the presynaptic cell-adhesion molecule Neurexin2 (Nrxn2). Given their crucial role in brain development and synpatic plasticity, this putative interaction is expected to highly impact neurotransmission and synaptic connections formation. Despite the extensive amount of studies on the function of both NMDAR and Nrxns, the putative interaction between GluN2B and Nrxn2 was never explored. Compelling research suggests cell-adhesion molecules impact postsynaptic receptors function, yet for the most part the molecular mechanisms involved are unknown. The molecular complex Nrxn2-GluN2B will be thoroughly investigated using a combination of bichemical, confocal and state-of-the-art super-resolution imaging and electrophysiology techniques. The interaction domains will be identified, and the consequences for interfering with this complex for synaptic physiology and animal behavior will be comprehensively examined.

Main Goals

The main goals of the project are to: 1) extensively characterize the novel complex binding, using a combination of biochemistry, molecular imaging approaches; 2) define the physiological role of this interaction, using different molecular replacement or knockdown strategies to evaluate the impact in protein clustering and nanoscale organization; 3) evaluate the effect of disrupting the interaction Nrxn2-GluN2B-NMDARs on synaptic transmission and animal behavior.

Project Details