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.
Highlights
SCHIZOPHRENIA AND GLYCINE NEUROTRANSMISSIONSchizophrenia (SCZ) is a chronic and debilitating severe mental disorder affecting approximately 0.3–0.7% of the population worldwide [1]
Postsynaptic density (PSD) is an electron-dense structure composed of glutamate receptors (NMDARs, AMPARs, mGluRs), proteins involved in signal transduction, scaffold proteins, and cytoskeletal structures localized at the distal tip of dendritic spines at excitatory synapses [172,173,174]
These authors found that polymorphisms within the gene encoding for D-amino acid oxidase (DAO), which partially mediates the degradation of D-serine, a component of the glutamatergic transmission and an endogenous ligand for the glycine B-site on N-Methyl-D-Aspartate receptor (NMDAR) [121], were statistically significantly associated with SCHIZOPHRENIA AND GLYCINE NEUROTRANSMISSIONSchizophrenia (SCZ) in a case-control study [197]
Summary
Schizophrenia (SCZ) is a chronic and debilitating severe mental disorder affecting approximately 0.3–0.7% of the population worldwide [1]. We aim to selectively review the preclinical and clinical evidence demonstrating that glycine, as well as the components of its signaling pathway, might be suitable targets for the identification of novel treatment strategies in severe psychiatric disorder and in SCZ. Potential implication of glycine signaling in the pathophysiology of SCZ is supported by a number of recent studies exploring genetic abnormalities within glycinergic system associated with SCZ as well as by the evidence of potential pro-cognitive and antipsychotic phenotype exhibited by animal models of Glycine Transporter type 1 (GlyT1) functional inhibition both by recombinant knock out [47] and pharmacological treatments [48, 49]. The recent finding of elevated brain glycine and glutamate levels in patients with first-episode psychosis, measured in vivo by means of echo time–averaged proton magnetic resonance spectroscopy (MRS) at 4 Tesla, further confirm the relevant role of glycine in the framework of multiple interacting neurotransmitters in SCZ pathophysiology [50]
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