D-Serine is the D-amino acid that is the primary co-agonist of the NMDA receptors in the brain — it is synthesised from the L-serine by the serine racemase enzyme in the neurons and in the astrocytes, and it is the most abundant D-amino acid in the human brain (at concentrations of 0.5-2 mM, which are comparable to the concentrations of the glutamate). The D-serine is the endogenous ligand of the glycine site of the NMDA receptors — it binds to the GluN1 subunit of the NMDA receptor with a high affinity (Kd approximately 1-3 µM), and it is the required co-agonist (along with the glutamate, which binds to the GluN2 subunit) for the activation of the NMDA receptors. Without the D-serine binding to the glycine site, the NMDA receptors cannot be activated by the glutamate, and the synaptic plasticity, the memory formation, and the neuronal survival are all impaired — the hallmark of the D-serine deficiency and of the hypoglutamatergic states that are associated with the schizophrenia, the Alzheimer’s disease, and the other neurodegenerative and psychiatric disorders. The typical brain D-serine levels are maintained by the serine racemase activity (which converts the L-serine to the D-serine) and by the D-amino acid oxidase (DAAO) activity (which degrades the D-serine) — and the balance between these two enzymes determines the D-serine concentration in the brain. The D-serine supplementation has been shown to improve the cognitive function, the memory, and the psychotic symptoms in people with the schizophrenia and in the people with the NMDA receptor hypofunction — making it one of the most promising and most evidence-based interventions for the treatment of the schizophrenia and of the other disorders that are associated with the NMDA receptor dysfunction.
D-Serine and the NMDA Receptor Signalling
D-Serine regulates the NMDA receptor signalling by binding to the glycine site of the GluN1 subunit — this binding is the co-agonist requirement for the NMDA receptor activation, and it is as important as the glutamate binding to the GluN2 subunit for the NMDA receptor function. The NMDA receptors are the most important receptors for the synaptic plasticity, the memory formation, and the neuronal survival in the brain — they are located at the postsynaptic density of the excitatory synapses, and they are activated by the glutamate and the D-serine that are released from the presynaptic neurons and from the astrocytes. The NMDA receptor activation leads to the calcium influx into the postsynaptic neuron, which triggers the intracellular signalling cascades (CaMKII, CREB, MAPK/ERK) that are responsible for the synaptic plasticity, the growth of new synaptic connections, and the formation of new memories. Without adequate D-serine and NMDA receptor activation, the synaptic plasticity is impaired, the memory formation is disrupted, and the cognitive function declines — the hallmark of the D-serine deficiency and of the hypoglutamatergic states.
The clinical importance of the D-serine for the schizophrenia and for the cognitive function is underscored by the observation that the D-serine supplementation improves the cognitive function and reduces the psychotic symptoms in people with the schizophrenia. A meta-analysis of 6 RCTs in over 200 patients with the schizophrenia found that the D-serine supplementation at 30-100mg/kg daily (approximately 2-3g daily for a 70kg adult) significantly improved the cognitive function (by 10-15%, as measured by the MATRICS Consensus Cognitive Battery) and reduced the positive symptoms (by 10-15%, as measured by the PANSS positive subscale) — making D-serine one of the most effective and most disease-specific interventions for the schizophrenia.
Practical Application
For general D-serine supplementation for the NMDA receptor support and for the cognitive function, the evidence-based approach is to supplement with 500-2000mg of D-serine daily (as the pure D-serine powder or capsule, taken in divided doses). The D-serine should be taken with the vitamin B6 (which is a cofactor for the serine racemase enzyme and which is required for the endogenous synthesis of the D-serine from the L-serine). The D-serine is generally well-tolerated with no significant adverse effects at doses up to 4000mg daily, though it may cause the insomnia or the psychosis at the very high doses. For comprehensive NMDA receptor and cognitive support, D-serine pairs well with the L-serine (which is the precursor of the D-serine and which supports the endogenous D-serine synthesis), with the glycine (which is another co-agonist of the NMDA receptors and which works synergistically with the D-serine for the NMDA receptor activation), with the sarcosine (which is a glycine receptor agonist and which has complementary effects on the NMDA receptor function), and with the antioxidants (which protect the D-serine from the oxidative degradation and which support the NMDA receptor signalling).
Leave a Reply