Endogenous D-serine exists in the mammalian brain independent of synthesis by serine racemase

Activation of N-methyl-_D-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to _L-glutamate. _D-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a _D-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of _D-serine in the brain remain unclarified. In the present study, we investigated the origin of brain _D-serine in mice. Loss of SR significantly reduced _D-serine in the cerebral cortex, but a portion of _D-serine remained in both neonates and adults. Although _D-serine was also produced by intestinal bacteria, germ-free experiments did not influence _D-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal _D-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of _D-serine and resulted in a slight decrease of _D-serine in the cerebral cortex, but did not account for brain _D-serine found in the SR-knockout mice. Therefore, our findings show that endogenous _D-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous _D-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.