In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory coagonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for Dserine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L-and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that Lserine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steadystate levels of D-serine in adult brain. Furthermore, NMDAevoked transcription of Arc, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of Dserine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.Glutamate is the principal excitatory neurotransmitter in mammalian brain, acting on ionotropic and metabotropic glutamate receptors. Ionotropic glutamate receptors can be divided into three classes based on their preference for the ligands N-methyl-D-aspartate (NMDA), 3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and kainate. Among these receptors, NMDA receptors have been implicated in synapse refinement, synaptic plasticity, and learning/memory as well as brain pathologies including excitotoxicity and psychiatric diseases (for review, see Refs. 1-3). Two NMDA receptor subunits, NR1 and NR2, form tetramers that comprise the functional receptors. For the NMDA receptor to function as a ligand-gated ion channel, a co-agonist must occupy the glycine modulatory site on NR1 coincident with glutamate binding to the transmitter recognition site on NR2 (4 -6).D-Serine occurs naturally in the adult brain of higher vertebrates and is particularly enriched in forebrain regions (7). This D-amino acid acts as an endogenous co-agonist at the glycine modulatory site of NMDA receptors (for review, see Refs. 8 -11). In the telencephalon, where D-serine is abundant (12), its distribution pattern resembles that of NR2A/B subunits (13). In contrast, immunoreactivity for free glycine is very low in telencephalon and is detected primarily in the hindbrain and hypothalamus, where NR2A/B expression is weaker than in ...

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Membrane lipid rafts provide a specialized microenvironment enriched with sphingolipids and phospholipids containing saturated fatty acids and serve as a platform for various intracellular signalling pathways. PtdGlc (phosphatidylglucoside) is a type of glycophospholipid localized in the outer leaflet of the plasma membrane. Owing to PtdGlc's unique fatty acid composition, exclusively composed of C(18:0) at sn-1 and C(20:0) at sn-2 of the glycerol backbone, it tends to form PGLRs (PtdGlc-enriched lipid rafts). Previously, we demonstrated that PGLRs reside on the cell surface of astroglial cells from fetal rat brain [Nagatsuka, Horibata, Yamazaki, Kinoshita, Shinoda, Hashikawa, Koshino, Nakamura and Hirabayashi (2006) Biochemistry 45, 8742-8750]. In the present study, we observed PGLRs in astroglial lineage cells at mid-embryonic to early-postnatal stages of developing mouse cortex. This suggests that PGLRs are developmentally correlated with astroglial differentiation during fetal cortical development. Our cell culture studies with multipotent neural progenitor cells prepared from fetal mouse telencephalon demonstrated that treatment with EGF (epidermal growth factor) or anti-PtdGlc antibody caused recruitment of EGFRs (EGF receptors) into lipid raft compartments, leading to activation of EGFRs. Moreover, the activation of EGFRs by antibody triggered downstream tyrosine kinase signalling and induced marked GFAP (glial fibrillary acidic protein) expression via the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway. These findings strongly suggest that PGLRs are physiologically coupled to activated EGFRs on neural progenitor cells during fetal cortical development, and thereby play a distinct role in mediating astrogliogenesis.

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NB-2, a neural cell recognition molecule of the contactin/F3 subgroup, promoted neurite outgrowth of the cerebral cortical neurons but not the hippocampal neurons. NB-2 in rat became apparent after birth at protein level, reaching a maximum at postnatal day 14 in the cerebrum and postnatal day 3 in the cerebellum. NB-2 in the cerebellum declined abruptly thereafter. In situ hybridization demonstrated that NB-2 mRNA was highly expressed in regions implicated in the central auditory pathway, including the cochlear nuclei, superior olive, inferior colliculi, medial geniculate nuclei, and auditory cortex. In addition, a high level of NB-2 expression was observed in the accessory olfactory bulb, thalamic nuclei, facial nucleus, and inferior olive. By immunohistochemistry, intense immunoreactivity against NB-2 was also detected in the auditory pathway. Thus, NB-2 is expressed in highly restricted brain regions, including the auditory system, suggesting that it plays specific roles in the development and/or maturation of the regions.