D-serine in health and disease

Abstract

Amino acids are among the most important molecules for living beings, since they are used to build peptides and proteins. Depending on their spatial positioning, amino acids can occur as D- or L-amino acids. This determines the function of peptides and proteins in the human body. It was long thought that only L-amino acids occurred in nature. In this respect, identification of the D-amino acid D-serine in the human brain was revolutionary. Moreover, D-serine appeared to function as a neurotransmitter by binding to the NMDA-receptor, similar to glycine. We developed two different analysis techniques to determine concentrations of D-serine (and glycine and other D- and L-amino acids) in biological fluids and determined reference ranges in cerebrospinal fluid from apparently healthy subjects. We observed very high D-serine concentrations directly after birth, both absolutely and relative to glycine and L-serine, followed by a rapid decline over the first 3 years to low adult values. Patients with the rare metabolic disorder 3-phosphoglycerate dehydrogenase deficiency fail to reach these high D-serine concentrations after birth and display severe neurological symptoms, including microcephaly, seizures and mental retardation. The one patient identified and treated pre- and postnatally did achieve high D-serine concentrations after birth and was born with a normal head circumference, no epilepsy and she develops well. The NMDA-receptor plays an important role in central nervous system development and we hypothesized that D-serine, as an NMDA-receptor agonist, might be essential in this respect. In fact, we demonstrate preliminary evidence for a role for D-serine in synaptogenesis in a P19 cell model for neuronal differentiation. The NMDA-receptor has also been implicated in numerous pathological conditions and we hypothesized that D-serine might play a role in these disorders, including perinatal asphyxia, one of the greatest causes of neonatal mortality and morbidity worldwide. We therefore investigated D-serine concentrations in rat glioma cells and in cerebrospinal fluid from piglets and human newborns after (simulated) hypoxia-ischemia. We observed significant increases in concentrations of both endogenous NMDAr co-agonists D-serine and glycine after hypoxia-ischemia, which in combination with the known elevated glutamate concentrations upon global ischemia are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently untreatable condition. Schizophrenia is another disease strongly associated with NMDAr dysfunction and potentially with altered D-serine concentrations. However, we found no differences in D-serine or glycine concentrations between cerebrospinal fluid from male patients with schizophrenia and controls before and after treatment with the antipsychotic drug olanzapine. This implies that cerebrospinal fluid D-serine and glycine concentrations do not represent an easy diagnostic or therapeutic marker for schizophrenia. Potentially, cerebrospinal fluid does not reflect subtle concentration differences in specific brain regions, which might be present in schizophrenia. In conclusion, the unexpected finding of D-serine in the human brain does not only challenge our conventional ideas on human physiology and pathology, but might also contribute to the development of novel diagnostic and therapeutic strategies.