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).
Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A. (2013) 110(26):E2400-2409.
Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, et al. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr. Res. (2007) 90:41–51.
Burnet PWJ, Eastwood SL, Bristow GC, Godlewska BR, Sikka P, Walker M, et al. D-amino acid oxidase activity and expression are increased in schizophrenia. Mol. Psychiatry (2008) 13:658–660.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc. Natl. Acad. Sci. USA (2002) 99:13675–13680.
Goltsov AY, Loseva JG, Andreeva TV, Grigorenko AP, Abramova LI, Kaleda VG, Orlova VA, Moliaka YK, Rogaev EI. Polymorphism in the 5’-promoter region of serine racemase gene in schizophrenia. Mol. Psychiatry (2006) 11:325–326.
Guercio GD, Panizzutti R. Potential and challenges for the clinical use of D-serine as a cognitive enhancer. Front. Psychiatry (2018) 5;9:14.
Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, et al. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch. Gen. Psychiatry (2003) 60:572–576.
Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindström LH, Iyo M. Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol. Biol. Psychiatry (2005) 29:767–769.
Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am. J. Psychiatry (1991) 148:1301–1308.
Labrie V, Fukumura R, Rastogi A, Fick LJ, Wang W, Boutros PC, Kennedy JL, Semeralul MO, Lee FH, Baker GB, Belsham DD, Barger SW, Gondo Y, Wong AH, Roder JC. Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model. Hum. Mol. Genet. (2009) 18:3227–3243.
Labrie V, Wang W, Barger SW, Baker GB, Roder JC. Genetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in mice. Genes Brain Behav. (2010) 9(1):11-25.
Lin C-H, Chang H-T, Chen Y-J, Lin C-H, Huang C-H, Tun R, et al. Distinctively higher plasma G72 protein levels in patients with schizophrenia than in healthy individuals. Mol. Psychiatry (2014) 19:636–637.
Madeira C, Freitas ME, Vargas-Lopes C, Wolosker H, Panizzutti R. Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr. Res. (2008) 101:76–83.
Molla G. Competitive inhibitors unveil structure/function relationships in human D-amino acid oxidase. Front. Mol. Biosci. (2017) 27;4:80.
Morita Y, Ujike H, Tanaka Y, Otani K, Kishimoto M, Morio A, Kotaka T, Okahisa Y, Matsushita M, Morikawa A, Hamase K, Zaitsu K, Kuroda S. A genetic variant of the serine racemase gene is associated with schizophrenia. Biol. Psychiatry (2007) 61:1200–1203.
Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, Kida S, Shibata N, Suzuki T, Arai H. Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol. Biol. Psychiatry. (2008) 12;32(8):1905-1912.
Pollegioni L, Sacchi S. Metabolism of the neuromodulator D-serine. Cell. Mol. Life Sci. (2010) 67(14):2387-2404.
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron (2006) 52:139–153.
Sacchi S, Bernasconi M, Martineau M, Mothet JP, Ruzzene M, Pilone MS, Pollegioni L, Molla G. pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: effect on schizophrenia susceptibility. J. Biol. Chem. (2008) 283(32):22244-22256.
Sacchi S, Rosini E, Pollegioni L, Molla G. D-amino acid oxidase inhibitors as a novel class of drugs for schizophrenia therapy. Curr. Pharm. Des. (2013) 19(14):2499-2511.
Sacchi S, Binelli G, Pollegioni L. G72 primate-specific gene: a still enigmatic element in psychiatric disorders. Cell. Mol. Life Sci. (2016) 73(10):2029-2039.
Loredano Pollegioni, Università degli studi dell’Insubria