Schizophrenia is a severe neuropsychiatric disorder affecting about 1% of the population worldwide. It is characterized by psychotic features (delusions, hallucinations, and disorganized thought), profound cognitive deficits (impairments in attention, learning, and memory) and negative symptoms (apathy and avolition).

Schizophrenia is known to be influenced by heritable factors, and genetic studies have identified a number of susceptibility genes that modulate NMDA receptor function (Ross et al., 2006). This indicates that deficient glutamatergic neurotransmission mediated by these receptors may be involved in the pathophysiology of schizophrenia. It is known that non-competitive antagonists of the NMDA receptors, such as phencyclidine, elicit schizophrenic-like symptoms in healthy individuals and exacerbate such symptoms in patients (Javitt et al., 1991). In schizophrenia affected patients a higher amount of anti-NMDA receptor antibodies were found in the serum as well as polymorphisms in the receptor subunits and reduced levels of the receptor subunits in post mortem samples from dorsolateral prefrontal cortex, for a review see (Guercio and Panizzutti, 2018).

An increasing body of evidences indicate that an alteration in D-serine level, a co-agonist of NMDA receptors which is enriched in prefrontal and parietal cortex (brain regions implicated in the pathogenesis of schizophrenia), may be involved in this disease. Actually, genetic mice models possessing lower D-serine levels (i.e. with mutations in the gene encoding serine racemase, SR, the enzyme that produces D-serine) show some traits of schizophrenia, such as sensorimotor gating and memory deficits: these deficits were increased by using an NMDA receptor antagonist and improved by treating with clozapine (an atypical antipsychotic) or D-serine.

A number of studies suggest that genes encoding proteins involved in D-serine metabolism – SR but also DAAO (encoding the enzyme deputed to D-serine degradation) and G72 (encoding pLG72 protein which modulates DAAO activity) – might potentially contribute to the pathogenesis of schizophrenia. An analysis of SNPs and haplotypes found an association between the G72 gene with schizophrenia (Chumakov et al., 2002), as well as for DAAO itself and for combinations of G72/DAAO genotypes which had a synergistic effect on disease risk. Both DAAO and G72 genes are located in chromosomal regions showing evidence for linkage with this disease. The majority of replication studies of G72 have indicated significant associations of alleles, genotypes, or haplotypes with schizophrenia in various populations, for a review see (Pollegioni and Sacchi, 2010; Sacchi et al., 2016). Notably, polymorphisms in the promoter and 5’-end of SR gene showed a significant association with schizophrenia (Goltsov et al., 2006; Morita et al., 2007; Labrie et al., 2009).

At the protein level, SR and SR/DAAO ratio were significantly decreased in frontal cortex and hippocampus, while the amount of DAAO in hippocampus was ~ 80% higher in patients who have been treated for over 20 years (Bendikov et al., 2007). Increased DAAO levels were measured in post mortem samples of the cerebellum and cerebral cortex of schizophrenic compared to healthy controls (Madeira et al., 2008; Burnet et al., 2008).

In patients affected with schizophrenia, decreased levels of D-serine were detected in blood (1.86 ± 0.53 vs. 2.28 ± 0.59 µM in healthy controls), cerebrospinal fluid and post mortem brain tissues (Hashimoto et al., 2003; Hashimoto et al., 2005; Bendikov et al., 2007): such a change was associated to altered levels of pLG72 (Chumakov et al., 2002; Lin et al., 2014), a protein able to affect the activity of DAAO (Sacchi et al., 2016). A combination of biochemical approaches demonstrated that binding of pLG72 to DAAO decreases the stability of the flavoenzyme (Sacchi et al., 2008; Sacchi et al., 2016): the DAAO hyperactivity due to loss of the negative control exerted by pLG72 interaction decreases D-serine concentration and causes hypofunction of NMDA receptors, thus predisposing individuals to schizophrenia (Sacchi et al., 2008; Sacchi et al., 2016).

Knock out mice models with reduced production of D-serine have schizophrenic symptoms (Balu et al., 2013) and knocking out DAAO (thus preventing degradation of D-serine) is rehabilitative (Labrie et al., 2010). Indeed, clinical remission of schizophrenia is accompanied by an increase in D-serine concentrations independent of supplementation (Ohnuma et al., 2008).

Considering that D-serine may be diminished in schizophrenia, D-serine administration, affecting the NMDA receptor function, has been proposed as add-on therapy to antipsychotic medications to reduce symptoms of schizophrenia. This approach showed some limitations, such as a large variability in blood D-serine levels (which shows a short half-life of ~ 4 hours). A second option to increase D-serine levels is based on the use of selective DAAO inhibitors to decrease the D-amino acid degradation. During past 10 years a number of molecules have been designed and tested, see (Sacchi et al., 2013; Molla, 2017).