Cellular Origin and Regulation of D-and L-Serine in in Vitro and in Vivo Models of Cerebral Ischemia

Abstract

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-Serine from L-Serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-Serine remain elusive. The D-/L-Serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-Serine is derived from neurons, while L-Serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-Serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-Serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…161 SRR-KO mice exhibited smaller infarct volumes and better functional recovery, compared with control mice, after experimental middle cerebral artery occlusion and reperfusion, indicating that D-serine deletion can, at least in stroke, be used as a neuroprotective strategy. 161 However, L-serine deletion does not necessarily enable neuroprotection.…”

“…Following the first report of the effect of SRR deletion on ischemic brain damage, we have evaluated the neuroprotective effect of the elimination of D‐serine in a mouse ischemic stroke model . SRR‐KO mice exhibited smaller infarct volumes and better functional recovery, compared with control mice, after experimental middle cerebral artery occlusion and reperfusion, indicating that D‐serine deletion can, at least in stroke, be used as a neuroprotective strategy . However, L‐serine deletion does not necessarily enable neuroprotection.…”

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for β-elimination function

“…Of particular interest to our laboratory (7)(8)(9)(10)(11)(12)(13), the gaseous neurotransmitter, H 2 S, produced by another PLP enzyme (CBS) in the brain also elicits an NMDA excitatory response (14), potentially via an adenylate cyclase-cAMPdependent protein kinase-mediated mechanism (15). Indeed, both SR and CBS have emerged as potential targets for ischemic stroke, because there is evidence that both D-serine (16,17) and H 2 S (18) promote neuronal infarction following such a stroke event. Elevated D-serine levels have also been associated with Alzheimer's disease (19) and ALS (20), suggesting that SR may emerge as a potential target for neurodegenerative disease.…”

Nuclear Compartmentalization of Serine Racemase Regulates d-Serine Production

“…SR knock-out (KO) mice display phenotypic abnormalities compatible with NMDAR hypofunction (24 -26). Furthermore, they are resistant to NMDAR-mediated neurotoxicity and ␤-amyloid-induced cell death in vivo (27), and are less susceptible to stroke damage upon middle cerebral artery occlusion (20,28).…”