Heterogeneity of D-Serine Distribution in the Human Central Nervous System

Abstract

D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation.

Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

“…85 d-Ser is detected at submillimolar levels (10-30% of total serine), especially in the forebrain area, in virtually all tested mammals, including primates. However, d-Ser has not been detected in fish, amphibians, or birds, [86][87][88][89] which supports the view that brain d-Ser is conserved in mammals and that this is evolutionally distinct from the other classes of vertebrates ( Fig. 3).…”

“…Indeed, the "old" brain areas such as the brainstem and cerebellum contain d-Ser at levels less than 1/10 of those found in the cerebrum in mammals. 88,89 The forebrain-shifted distribution of d-Ser is determined by the activities of two principal enzymes: SR and d-amino acid oxidase (DAO). d-Ser is converted from l-Ser by SR, which was first purified by Wolosker in 1999.…”

Investigating brain d‐serine: Advocacy for good practices

“…Such a measurement needs careful experimental design, appropriate analytical techniques and proper execution in order to be confident in differentiating D-serine from other amino acids and from its L-enantiomer in biological samples. Analytical methods have matured, and we now have an array of techniques ranging from biosensors, [25][26][27] high pressure liquid chromatography (HPLC) [28][29][30] and LC/ LC 31 to LC/mass spectrometry 32,33 or capillary electrophoresis-laser-induced fluorescence (CE-LIF) [34][35][36] with well described protocols to detect and measure D-AAs (including D-serine) even at very low levels in complex matrices like biological samples. Despite the availability of multiple approaches to confirm D-serine, analysis of recent publications suggests that this D-AA was not always quantified with the controls that are outlined in Box 1 and Figure 1.…”

“…Since L-serine does not affect NMDAR activity on its own, this result should support the view at first glance that FAC poisoning of astrocytes could affect the synthesis and/ or the supply of L-serine to neurons. Restoring the glia-neuron shuttling by providing the D-serine precursor to neurons 30 (modified with permission). A shoulder on a peak as illustrated in panel A from 52 (modified with permission) is the sign of poorly resolved peaks, not allowing a conclusion.…”

d-Amino acids and kidney diseases

“…SR is predominantly expressed in the neurons of the forebrain [24,25]. In agreement with the localization of the enzyme, d-serine is most abundant in cerebrum [13,29]. In the brain, d-serine serves as a neurotransmitter of N-methyl-d-aspartate (NMDA)-type glutamate receptor (NMDAR) which maintains synaptic plasticity [30].…”