Project R-12277

Title

Enlightening the Glycine Receptor α2 as a key regulator in the brain reward-pathway

Abstract

The identification of subcellular localization of ion channels is crucial to understand its role. In this project, we aim to elucidate the subcellular location and dynamics of the glycine alpha 2 receptor (GlyRα2) within the striatum. This is a deep brain structure that orchestrates reward-motivated behavior. Its impairment underlies several psychiatric diseases, including psychosis and addiction. The main type of striatal neurons, medium spiny neurons (MSNs) are a convergence point for glutamatergic and dopaminergic input. Signal integration within MSN coordinates reward-motivated behavior. GlyRα2 modulates MSN activity and function, thus, targeting GlyRα2 offers great potential to modulate striatum-orchestrated behavior. We hypothesize that GlyRα2 are located extrasynaptically and activation of these GlyRα2 serves an inhibitory role to attenuate exaggerated MSN activity, and consequently prevent hyper-motivated behavior. We will address this by fusing a genetically encoded yellow fluorescent protein-based Cl-sensor to GlyRα2 and analyze this pioneering tool in vitro, in vivo and ex vivo using combined electrophysiology and high-resolution fluorescence. This innovative tool allows for investigation of subcellular localization and dynamics of the GlyRα2, and its function at the network and behavioral level. This project will provide vital insight into glycinergic modulation of striatal function and investigates the potential of GlyRα2 as a novel therapeutic target.

Period of project

01 November 2021 - 31 October 2023