Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain.
In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory co-agonist 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 D-serine 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 L-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of D-serine in adult brain. Furthermore, NMDA-evoked 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 D-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus.
Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, Fukuoka 812-8581, Japan.
Jung Hoon
JH
Yang
Akira
A
Wada
Kazuyuki
K
Yoshida
Yurika
Y
Miyoshi
Tomoko
T
Sayano
Kayoko
K
Esaki
Masami O
MO
Kinoshita
Shozo
S
Tomonaga
Norihiro
N
Azuma
Masahiko
M
Watanabe
Kenji
K
Hamase
Kiyoshi
K
Zaitsu
Takeo
T
Machida
Albee
A
Messing
Shigeyoshi
S
Itohara
Yoshio
Y
Hirabayashi
Shigeki
S
Furuya
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000737:chemistry*; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics*; D010766:Phosphorylation; D012559:Schizophrenia / Q000378:metabolism; D012694:Serine / Q000737:chemistry* / Q000378:metabolism
D012694:Serine; D016202:N-Methylaspartate; D050543:Phosphoglycerate Dehydrogenase