Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia

Abstract

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine - glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

Keywords: Homer; N-methyl-d-aspartate; PSD-95; antipsychotics; disk-1; dopamine; glutamate; glycine transporter 1.

Figure 1

Glycine Transporters and the Postsynaptic Density (PSD). GlyT1 is localized at the PSD of asymmetric glutamatergic synapses, belonging to a protein complex including NMDAR. PSD-95 physically interacts with GlyT1, stabilizing its localization at postsynaptic membrane. CaMKII may regulate GlyT1 activity via indirect phosphorylation mechanisms. Glycine may be released in the synaptic cleft also by astroglial cells via functional reversal of GlyT1. GlyT1: Glycine Receptor Transporter 1; NMDAR: N-Methyl-D-aspartate receptors; PSD-95: postsynaptic density protein 95; CaMKII: Ca2+/calmodulin-dependent protein kinase; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; mGluR type I: metabotropic glutamate receptors type I.