Synaptic vs. Non-Synaptic Glycine Receptors: Physiological Role and Implications in Alzheimer's Disease Pathology

Strychnine-sensitive glycine receptors (GlyRs) are pentameric ligand-gated chloride channels that mediate fast inhibitory neurotransmission in the central nervous system (CNS), with high expression in the spinal cord, brainstem, cerebellum, and retina. Beyond traditional postsynaptic phasic inhibition, emerging evidence highlights the importance of extrasynaptic GlyRs-expressed in both neuronal and non-neuronal cells-in mediating tonic inhibition by sensing ambient glycine levels, including in the forebrain. These non-synaptic receptors display high agonist affinity, unique subunit compositions, and distinct pharmacodynamics. Notably, recent studies have begun to implicate aberrant GlyR signaling in Alzheimer's disease (AD) pathology; however, its functional role in this specific neurodegenerative context remains only poorly understood. This review synthesizes the molecular properties and functional significance of these diverse GlyR populations, emphasizing their involvement in calcium signaling, inhibitory tone, and neural circuit modulation, while critically evaluating their emerging therapeutic potential in AD.