D-Serine Influences Synaptogenesis in a P19 Cell Model

Abstract

Recently, D-serine has been identified as an important NMDA-receptor co-agonist, which might play a role in central nervous system development. We investigated this by studying rat P19 cells, an established model for neuronal and glial differentiation. Our results show that (1) the D-serine synthesizing enzyme serine racemase was expressed upon differentiation, (2) extracellular D-serine concentrations increased upon differentiation, which was inhibited by serine racemase antagonism, and (3) inhibition of D-serine synthesis or prevention of D-serine binding to the NMDA-receptor increased synaptophysin expression and intercellular connections, supporting a role for NMDA-receptor activation by D-serine, synthesized by serine racemase, in shaping synaptogenesis and neuronal circuitry during central nervous system development. In conjunction with recent evidence from literature, we therefore suggest that D-serine deficiency might be responsible for the severe neurological phenotype seen in patients with serine deficiency disorders. In addition, this may provide a pathophysiological mechanism for a role of D-serine deficiency in psychiatric disorders.

The Postnatal Development of d-Serine in the Retinas of Two Mouse Strains, Including a Mutant Mouse with a Deficiency in d-Amino Acid Oxidase and a Serine Racemase Knockout Mouse

“… 39 , 40 In addition, d -serine has been identified as a critical regulator of postnatal development in other CNS regions, 41 , 42 specifically influencing NMDAR participation in synaptic activity with prolonged effects. 10 , 43 Finally, two studies suggest the sufficiency of neonatal d -serine changes to permanently impact on adult glutamatergic function. Mice with a 3-PGDH deficiency lack both l -serine and d -serine throughout their lives, but in one investigation maternal d -serine supplementation alone was able to completely reverse the otherwise abnormal neurological phenotype.…”

“…Mice with a 3-PGDH deficiency lack both l -serine and d -serine throughout their lives, but in one investigation maternal d -serine supplementation alone was able to completely reverse the otherwise abnormal neurological phenotype. 10 , 44 In another study, an SRR inhibitor was administered to rats from P7 to P9, which led to adult behavioral deficits despite a normal amino acid profile in multiple brain regions. Deficits in this latter model were consistent with schizophrenia, similar to our SR –/– mouse, and could be rescued by preadulthood treatment with d -serine.…”

“…d -Serine, NMDARs, and the d -serine regulatory enzymes, d -amino acid oxidase (DAO) and SR, have been implicated in multiple aspects of nervous system development, including regulation of dendritic morphology in pyramidal neurons, 7 cell migration in the cerebellar cortex, 8 , 9 and shaping synaptogenesis and neuronal circuitry. 10 d -Serine was more recently identified in the retina, 11 where it, rather than glycine, is the principal endogenous coagonist of NMDARs on retinal ganglion cells (RGCs). 12 , 13 Importantly, the coagonist sites of NMDA receptors in ganglion cells remain subsaturated, positioning the sensitivity of NMDA receptors to be further modulated by coagonist introduction, as evidenced by exogenously applied d -serine enhancing light-evoked NMDA receptor currents in RGCs.…”

d-Amino Acid Levels in Perfused Mouse Brain Tissue and Blood: A Comparative Study

“…D-Serine was found to be a coagonist of the Nmethyl-D-aspartate (NMDA)-type glutamate receptor, which could occupy the glycine binding site. 19,20 Free D-serine has been determined to be localized primarily in the mammalian forebrain, where the highest concentrations for NMDA receptors are found. 21−23 In cases with treatment-resistant depression, D-serine has been used as a potential biomarker of ketamine antidepressant response.…”

Impact of Aging in Microglia-Mediated D-Serine Balance in the CNS

“…This role is particularly important at early stages, where an elevated concentration of D-serine [ 95 , 120 ] encounters a transient elevated activity of NMDAR [ 94 ]. In murine P19 cells, an embryonic carcinoma cell line that can be differentiated to resemble neurons with functional glutamatergic receptors [ 121 ], D-serine induces synaptogenesis and serine racemase is very active [ 122 ]. D-serine released by astrocytes acts also as a chemokine for migration of granule cells in the cerebellum [ 123 ], and, at embryonic and early postnatal development, its decrease compromised the adequate lamination of the cerebellar cortex [ 124 ].…”